3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands

ABSTRACT

There are disclosed compounds of the formula 
                         
or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation in part of U.S. application Ser. No.10/241,326 filed Sep. 11, 2002 now abandoned, which in turn is acontinuation in part of U.S. application Ser. No. 10/208,412 filed Jul.30, 2002 now abandoned, which in turn is a continuation in part of U.S.application Ser. No. 10/122,841 filed Apr. 15, 2002 now abandoned, whichin turn claims the benefit U.S. Provisional Application 60/284,026,filed Apr. 16, 2001, the disclosures of which are incorporated herein byreference thereto.

FIELD OF THE INVENTION

The present invention relates to novel substituted cyclobutenedionecompounds, pharmaceutical compositions containing the compounds, and theuse of the compounds and formulations in treating CXC chemokine-mediateddiseases.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract macrophages, T-cells, eosinophils, basophils,neutrophils and endothelial cells to sites of inflammation and tumorgrowth. There are two main classes of chemokines, the CXC-chemokines andthe CC-chemokines. The class depends on whether the first two cystepnesare separated by a single amino acid (CXC-chemokines) or are adjacent(CC-chemokines). The CXC-chemokines include interleukin-8 (IL-8),neutrophil-activating protein-1 (NAP-1), neutrophil-activating protein-2(NAP-2), GROα, GROβ, GROγ, ENA-78, GCP-2, IP-10, MIG and PF4. CCchemokines include RANTES, MIP-1α, MIP-2β, monocyte chemotacticprotein-1 (MCP-1), MCP-2, MCP-3 and eotaxin. Individual members of thechemokine families are known to be bound by at least one chemokinereceptor, with CXC-chemokines generally bound by members of the CXCRclass of receptors, and CC-chemokines by members of the CCR class ofreceptors. For example, IL-8 is bound by the CXCR-1 and CXCR-2receptors.

Since CXC-chemokines promote the accumulation and activation ofneutrophils, these chemokines have been implicated in a wide range ofacute and chronic inflammatory disorders including psoriasis andrheumatoid arthritis. Baggiolini et al., FEBS Lett. 307, 97 (1992);Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al.,Annu. Fev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87,463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992);Donnely et al., Lancet 341, 643(1993).

ELRCXC chemokines including IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78(Strieter et al. 1995 JBC 270 p. 27348–57) have also been implicated inthe induction of tumor angiogenesis (new blood vessel growth). All ofthese chemokines are believed to exert their actions by binding to the 7transmembrane G-protein coupled receptor CXCR2 (also known as IL-8RB),while IL-8 also binds CXCR1 (also known as IL-8RA). Thus, theirangiogenic activity is due to their binding to and activation of CXCR2,and possible CXCR1 for IL-8, expressed on the surface of vascularendothelial cells (ECs) in surrounding vessels.

Many different types of tumors have been shown to produce ELRCXCchemokines and their production has been correlated with a moreaggressive phenotype (Inoue et al. 2000 Clin Cancer Res 6 p. 2104–2119)and poor prognosis (Yoneda et. al. 1998 J Nat Cancer Inst 90 p.447–454). Chemokines are potent chemotactic factors and the ELRCXCchemokines have been shown to induce EC chemotaxis. Thus, thesechemokines probably induce chemotaxis of endothelial cells toward theirsite of production in the tumor. This may be a critical step in theinduction of angiogenesis by the tumor. Inhibitors of CXCR2 or dualinhibitors of CXCR2 and CXCR1 will inhibit the angiogenic activity ofthe ELRCXC chemokines and therefore block the growth of the tumor. Thisanti-tumor activity has been demonstrated for antibodies to IL-8(Arenberg et al. 1996 J Clin Invest 97 p. 2792–2802), ENA-78 (Arenberget al. 1998 J Clin Invest 102 p. 465–72), and GROα (Haghnegahdar et al.J. Leukoc Biology 2000 67 p. 53–62).

Many tumor cells have also been shown to express CXCR2 and thus tumorcells may also stimulate their own growth when they secrete ELRCXCchemokines. Thus, along with decreasing angiogenesis, inhibitors ofCXCR2 may directly inhibit the growth of tumor cells.

Hence, the CXC-chemokine receptors represent promising targets for thedevelopment of novel anti-inflammatory and anti-tumor agents.

There remains a need for compounds that are capable of modulatingactivity at CXC-chemokine receptors. For example, conditions associatedwith an increase in IL-8 production (which is responsible for chemotaxisof neutrophil and T-cell subsets into the inflammatory site and growthof tumors) would benefit by compounds that are inhibitors of IL-8receptor binding.

SUMMARY OF THE INVENTION

This invention provides a method of treating a chemokine mediateddisease in a patient in need of such treatment comprising administeringto said patient an effective amount of a compound of formula IA, asdescribed below

This invention also provides a method of treating cancer in a patient inneed of such treatment comprising administering to said patient aneffective amount of a compound of formula IA, as described below.

This invention also provides a method of treating cancer in a patient inneed of such treatment comprising administering to said patient aneffective amount of a compound of formula IA, as described below,concurrently or sequentially with: (a) a microtubule affecting agent, or(b) an antineoplastic agent, or (c) an anti-angiogenesis agent, or (d) aVEGF receptor kinase inhibitor, or (e) antibodies against the VEGFreceptor, or (f) interferon, and/or g) radiation.

This invention also provides a method of inhibiting angiogenesis, in apatient in need of such treatment, comprising administering to saidpatient an effective amount of at least one compound of formula IA, asdescribed below.

This invention also provides a method of treating angiogenic oculardisease (e.g., ocular inflammation, retinopathy of prematurity, diabeticretinopathy, macular degeneration with the wet type preferred andcorneal neovascularization) in a patient in need of such treatment,comprising administering to said patient an effective amount of at leastone compound of formula IA, as described below.

This invention also provides a method of treating a disease selectedfrom the group consisting of: gingivitis, respiratory viruses, herpesviruses, hepatitis viruses, HIV, kaposi's sarcoma associated virus andatherosclerosis, in a patient in need of such treatment, comprisingadministering to said patient an effective amount of at least onecompound of formula IA, as described below.

This invention also provides a method of treating acute inflammatorypain, in a patient in need of such treatment, comprising administeringto said patient an effective amount of at least one compound of formulaIA, as described below.

This invention also provides a method of treating chronic inflammatorypain, in a patient in need of such treatment, comprising administeringto said patient an effective amount of at least one compound of formulaIA, as described below.

This invention also provides a method of treating acute neuropathicpain, in a patient in need of such treatment, comprising administeringto said patient an effective amount of at least one compound of formulaIA, as described below.

This invention also provides a method of treating chronic neuropathicpain, in a patient in need of such treatment, comprising administeringto said patient an effective amount of at least one compound of formulaIA, as described below.

This invention also provides a method of treating COPD, in a patient inneed of such treatment, comprising administering to said patient andeffective amount of at least one compound of formula IA as describedbelow.

This invention also provides a method of treating acute inflammation, ina patient in need of such treatment, comprising administering to saidpatient and effective amount of at least one compound of formula IA asdescribed below.

This invention also provides a method of treating chronic inflammation,in a patient in need of such treatment, comprising administering to saidpatient and effective amount of at least one compound of formula IA asdescribed below.

This invention also provides a method of treating rheumatoid arthritis,in a patient in need of such treatment, comprising administering to saidpatient and effective amount of at least one compound of formula IA asdescribed below.

This invention also provides novel compounds of formula IA, as describedbelow.

This invention also provides a pharmaceutical composition comprising atleast one (e.g., 1–3, usually 1) compound of formula IA, as describedbelow, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

When any variable occurs more than one time in any moiety, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

Unless indicated otherwise, the following definitions apply throughoutthe present specification and claims. These definitions apply regardlessof whether a term is used by itself or in combination with other terms.For example, the definition of “alkyl” also applies to the “alkyl”portion of “alkoxy”.

“At least one” represents, for example, 1, or 1–2, or 1–3.

“Patient” includes both human and other mammals, preferably human.

“Mammal” includes a human being, and preferably means a human being.

“Alkyl” means a straight or branched saturated hydrocarbon chain having1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1to 6 carbon atoms.

“Alkoxy” means an alkyl-O-group wherein alkyl is as defined above.Non-limiting examples of alkoxy groups include: methoxy, ethoxy,n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety isthrough the ether oxygen.

“Alkenyl” means a straight or branched aliphatic hydrocarbon grouphaving at least one carbon-carbon double bond, and 2 to 20 carbon atoms,preferably 2 to 12 carbon atoms, and more preferably 2 to 6 carbonatoms. Non-limiting examples of alkenyl groups include: ethenyl,propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl anddecenyl.

“Alkynyl” means a straight or branched aliphatic hydrocarbon grouphaving at least one carbon-carbon triple bond, and 2 to 15 carbon atoms,preferably 2 to 12 carbon atoms, and more preferably 2 to 4 carbonatoms. Non-limiting examples of alkynyl groups include ethynyl,propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” means an aromatic monocyclic or multicyclic ring system, whereinat least one ring is aromatic, comprising about 6 to about 14 carbonatoms, and preferably about 6 to about 10 carbon atoms. Non-limitingexamples of suitable aryl groups include: phenyl, naphthyl, indenyl,tetrahydronaphthyl, indanyl, anthracenyl, and fluorenyl.

“Arylalkyl” means an aryl group, as defined above, bound to an alkylgroup, as defined above, wherein the alkyl group is bound to the parentmoiety. Non-limiting examples of suitable arylalkyl groups includebenzyl, phenethyl and naphthleneylmethyl.

“Cycloalkyl” means saturated carbocyclic rings having 3 to 10 (e.g., 3to 7) carbon atoms, preferably 5 to 10 carbon atoms, and more preferably5 to 7 carbon atoms, and having one to three rings. Non-limitingexamples of cycloalkyl groups include: cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

“Cycloalkylalkyl” means a cycloalkyl group bound to the parent moietythrough an alkyl group. Non-limiting examples include: cyclopropylmethyland cyclohexylmethyl.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising 3 to 10 carbon atoms, and preferably 5 to 10 carbon atoms,and having at least one carbon-carbon double bond. Preferredcycloalkenyl rings have 5 to 7 carbon atoms. Non-limiting examples ofcycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,and norbornenyl.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine or bromine, and more preferred are fluorine andchlorine.

“Haloalkyl” means an alkyl group as defined above wherein one or morehydrogen atoms on the alkyl is replaced by a halo group defined above.

“Heterocyclyl” or “heterocyclic” or “heterocycloalkyl” means anon-aromatic saturated monocyclic or multicyclic ring system (i.e., asaturated carbocyclic ring or ring system) comprising 3 to 10 ring atoms(e.g., 3 to 7 ring atoms), preferably 5 to 10 ring atoms, in which oneor more of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls have 5 to 6 ring atoms. The prefix aza, oxa orthia before the heterocyclyl root name means that at least a nitrogen,oxygen or sulfur atom, respectively, is present as a ring atom. Thenitrogen or sulfur atom of the heterocyclyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limitingexamples of monocyclic heterocyclyl rings include: piperidyl,pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,and tetrahydrothiopyranyl.

The term heterocyclic acidic functional group is intended to includegroups such as, pyrrole, imidazole, triazole, tetrazole, and the like.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in whichone or more of the ring atoms is an element other than carbon, forexample nitrogen, oxygen or sulfur, alone or in combination. Preferredheteroaryls contain 5 to 6 ring atoms. The prefix aza, oxa or thiabefore the heteroaryl root name means that at least a nitrogen, oxygenor sulfur atom respectively, is present as a ring atom. A nitrogen atomof a heteroaryl can be optionally oxidized to the corresponding N-oxide.Non-limiting examples of heteroaryls include: pyridyl, pyrazinyl,furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl,thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, and benzothiazolyl.

“Heteroarylalkyl” means a heteroaryl group, as defined above, bound toan alkyl group, as defined above, where the bond to the parent moiety isthrough the alkyl group.

N-oxides can form on a tertiary nitrogen present in an R substituent, oron ═N— in a heteroaryl ring substituent and are included in thecompounds of formula I.

The term “prodrug,” as used herein, represents compounds which arerapidly transformed in vivo to the parent compound of the above formula,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

As used in the methods of this invention, “an effective amount” means atherapeutically acceptable amount (i.e., that amount which provides thedesired therapeutic effective).

Also, as used herein, with reference to chemical structures or formulas,“Bn” represents benzyl, “Et” represents ethyl, “Me” represents methyl,and “Ph” represents phenyl.

Representative embodiments of this invention are described below. Theembodiments have been numbered for purposes of reference thereto.

The methods of this invention use a compound of formula IA:

and the pharmaceutically acceptable salts (e.g., sodium or calcium salt)and solvates thereof, wherein:

A is selected from the group consisting of:

wherein the above rings of said A groups are substituted with 1 to 6substituents each independently selected from the group consisting of:R⁹ groups;

wherein one or both of the above rings of said A groups are substitutedwith 1 to 6 substituents each independently selected from the groupconsisting of: R⁹ groups;

wherein the above phenyl rings of said A groups are substituted with 1to 3 substituents each independently selected from the group consistingof: R⁹ groups; and

B is selected from the group consisting of

n is 0 to 6;

p is 1 to 5;

X is O, NH, or S;

Z is 1 to 3;

R² is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH,—SO₂NR¹³R¹⁴, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —NR¹³R¹⁴,—C(O)NR¹³R¹⁴, —C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³, anunsubstituted heterocyclic acidic functional group, and a substitutedheterocyclic acidic functional group; wherein there are 1 to 6substituents on said substituted heterocyclic acidic functional groupeach substituent being independently selected from the group consistingof: R⁹ groups;

each R³ and R⁴ is independently selected from the group consisting of:hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂,—C(O)R¹³, —C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—SO_((t))R¹³, —C(O)NR¹³OR¹⁴, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl,

wherein there are 1 to 6 substituents on said substituted aryl group andeach substituent is independently selected from the group consisting of:R⁹ groups; and wherein there are 1 to 6 substituents on said substitutedheteroaryl group and each substituent is independently selected from thegroup consisting of: R⁹ groups;

each R⁵ and R⁶ are the same or different and are independently selectedfrom the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF₃,—OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—C(O)NR¹³OR¹⁴, cyano, unsubstituted or substituted aryl, andunsubstituted or substituted heteroaryl group; wherein there are 1 to 6substituents on said substituted aryl group and each substituent isindependently selected from the group consisting of: R⁹ groups; andwherein there are 1 to 6 substituents on said substituted heteroarylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups;

each R⁷ and R⁸ is independently selected from the group consisting of:H, unsubstituted or substituted alkyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, alkynyl, alkenyl, andcycloalkenyl; and wherein there are one or more (e.g., 1 to 6)substituents on said substituted R⁷ and R⁸ groups, wherein eachsubstitutent is independently selected from the group consisting of:

-   -   a) halogen,    -   b) —CF₃,    -   c) —COR¹³,    -   d) —OR¹³,    -   e) —NR¹³R¹⁴,    -   f) —NO₂,    -   g) —CN,    -   h) —SO₂OR¹³,    -   i) —Si(alkyl)₃, wherein each alkyl is independently selected,    -   j) —Si(aryl)₃, wherein each alkyl is independently selected,    -   k) —(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected,    -   l) —CO₂R¹³,    -   m) —C(O)NR¹³R¹⁴,    -   n) —SO₂NR¹³R¹⁴,    -   o) —SO₂R¹³,    -   p) —OC(O)R¹³,    -   q) —OC(O)NR¹³R¹⁴,    -   r) —NR¹³C(O)R¹⁴, and    -   s) —NR¹³CO₂R¹⁴;        (fluoroalkyl is one non-limiting example of an alkyl group that        is substituted with halogen);

R^(8a) is selected from the group consisting of: hydrogen, alkyl,cycloalkyl and cycloalkylalkyl;

each R⁹ is independently selected from the group consisting of:

-   -   a) —R¹³,    -   b) halogen,    -   c) —CF₃,    -   d) —COR¹³,    -   e) —OR¹³,    -   f) —NR¹³R¹⁴,    -   g) —NO₂,    -   h) —CN,    -   i) —SO₂R¹³,    -   j) —SO₂NR¹³R¹⁴,    -   k) —NR¹³COR¹⁴,    -   l) —CONR¹³R¹⁴,    -   m) —NR¹³CO₂R¹⁴,    -   n) —CO₂R¹³,

-   -   p) alkyl substituted with one or more (e.g., one) —OH groups        (e.g., —(CH₂)_(q)OH, wherein q is 1–6, usually 1 to 2, and        preferably 1),    -   q) alkyl substituted with one or more (e.g., one) —NR¹³R¹⁴ group        (e.g., —(CH₂)_(q)NR¹³R¹⁴, wherein q is 1–6, usually 1 to 2, and        preferably 1), and    -   r) —N(R¹³)SO₂R¹⁴ (e.g., R¹³ is H and R¹⁴ is alkyl, such as        methyl);

each R¹⁰ and R¹¹ is independently selected from the group consisting ofR¹³, hydrogen, alkyl (e.g., C₁ to C₆, such as methyl), halogen, —CF₃,—OCF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —OH, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³ and cyano;

R¹² is selected from the group consisting of: hydrogen, —C(O)OR¹³,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted cycloalkyl, unsubstituted or substituted alkyl,unsubstituted or substituted cycloalkylalkyl, and unsubstituted orsubstituted heteroarylalkyl group; wherein there are 1 to 6 substituentson the substituted R¹² groups and each substituent is independentlyselected from the group consisting of: R⁹ groups;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, unsubstituted or substituted alkyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, unsubstituted or substituted heterocyclic,unsubstituted or substituted fluoroalkyl, and unsubstituted orsubstituted heterocycloalkylalkyl (wherein “heterocyloalkyl” meansheterocyclic); wherein there are 1 to 6 substituents on said substitutedR¹³ and R¹⁴ groups and each substituent is independently selected fromthe group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl,fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,—N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, halogen, and —NHC(O)NR¹⁵R¹⁶; or

R¹³ and R¹⁴ taken together with the nitrogen they are attached to in thegroups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted or substitutedsaturated heterocyclic ring (preferably a 3 to 7 membered heterocyclicring), said ring optionally containing one additional heteroatomselected from the group consisting of: O, S and NR¹⁸; wherein there are1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., there is 1 to 3 substituents on the ring formed when the R¹³ andR¹⁴ groups are taken together with the nitrogen to which they are bound)and each substituent is independently selected from the group consistingof: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and aheterocycloalkenyl group (i.e., a heterocyclic group that has at leastone, and preferably one, double bond in a ring, e.g.,

each R¹⁵ and R¹⁶ is independently selected from the group consisting of:H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

R¹⁷ is selected from the group consisting of: —SO₂alkyl, —SO₂aryl,—SO₂cycloalkyl, and —SO₂heteroaryl;

R¹⁸ is selected from the group consisting of: H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰;

each R¹⁹ and R²⁰ is independently selected from the group consisting of:alkyl, aryl and heteroaryl;

R³⁰ is selected from the group consisting of: alkyl, cycloalkyl, —CN,—NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H;

each R³¹ is independently selected from the group consisting of:unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted cycloalkyl;wherein there are 1 to 6 substituents on said substituted R³¹ groups andeach substituent is independently selected from the group consisting of:alkyl, halogen and —CF₃;

each R⁴⁰ is independently selected from the group consisting of: H,alkyl and cycloalkyl; and

t is 0, 1 or 2.

An embodiment of the present invention is directed to a method oftreating a chemokine mediated disease in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1–3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

Examples of chemokine mediated diseases include: acute inflammation,chronic inflammation, rheumatoid arthritis, acute inflammatory pain,chronic inflammatory pain, acute neuropathic pain, chronic neuropathicpain, psoriasis, atopic dermatitis, asthma, COPD, adult respiratorydisease, arthritis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis,toxic shock syndrome, stroke, cardiac and renal reperfusion injury,glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. hostreaction, allograft rejections, malaria, acute respiratory distresssyndrome, delayed type hypersensitivity reaction, atherosclerosis,cerebral and cardiac ischemia, osteoarthritis, multiple sclerosis,restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses,herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associatedvirus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis,multi-organ dysfunction, trauma, strains, sprains, contusions, psoriaticarthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury,CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitialpneumonitis, hypersensitivity, crystal induced arthritis, acute andchronic pancreatitis, acute alcoholic hepatitis, necrotizingenterocolitis, chronic sinusitis, angiogenic ocular disease, ocularinflammation, retinopathy of prematurity, diabetic retinopathy, maculardegeneration with the wet type preferred and corneal neovascularization,polymyositis, vasculitis, acne, gastric and duodenal ulcers, celiacdisease, esophagitis, glossitis, airflow obstruction, airwayhyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitisobliterans, chronic bronchitis, cor pulmonae, cough, dyspnea, emphysema,hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations,hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonaryhypertension, right ventricular hypertrophy, peritonitis associated withcontinuous ambulatory peritoneal dialysis (CAPD), granulocyticehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusionmismatching, wheeze, colds, gout, alcoholic liver disease, lupus, bumtherapy, periodontitis, transplant reperfusion injury and earlytransplantation rejection.

An embodiment of the present invention is directed to a method oftreating cancer in a patient (e.g., a mammal, such as a human being) inneed of such treatment, comprising administering to said patient,concurrently or sequentially, a therapeutically effective amount of (a)at least one (e.g., 1–3, and usually one) compound of formula IA, and(b) a microtubule affecting agent or antineoplastic agent oranti-angiogenesis agent or VEGF receptor kinase inhibitor or antibodiesagainst the VEGF receptor or interferon, and/or c) radiation.

In further embodiments directed to the treatment of cancer, at least one(e.g., 1–3, and usually one) compound of formula IA is administered incombination with antineoplastic agents (e.g., one or more, such as one,or such as one or two), selected from the group consisting of:gemcitabine, paclitaxel (Taxol®), 5-Fluorouracil (5-FU),cyclophosphamide (Cytoxan®), temozolomide, taxotere and Vincristine.

In another embodiment the present invention provides a method oftreating cancer in a patient (e.g., a mammal, such as a human being) inneed of such treatment, comprising administering, concurrently orsequentially, an effective amount of (a) a compound of formula IA, and(b) a microtubule affecting agent (e.g., paclitaxel).

Another embodiment of the present invention is directed to a method oftreating acute inflammatory pain, in a patient in need of such treatment(e.g., a mammal, preferably a human being) comprising administering tosaid patient a therapeutically effective amount of at least one (e.g.,1–3, and usually one) compound of formula IA, or a pharmaceuticallyacceptable salt or solvate thereof.

Another embodiment of the present invention is directed to a method oftreating chronic inflammatory pain, in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1–3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

Another embodiment of the present invention is directed to a method oftreating acute neuropathic pain, in a patient in need of such treatment(e.g., a mammal, preferably a human being) comprising administering tosaid patient a therapeutically effective amount of at least one (e.g.,1–3, and usually one) compound of formula IA, or a pharmaceuticallyacceptable salt or solvate thereof.

Another embodiment of the present invention is directed to a method oftreating chronic neuropathic pain, in a patient in need of suchtreatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1–3, and usually one) compound of formula IA, or apharmaceutically acceptable salt or solvate thereof.

Another embodiment of the present invention is directed to a method oftreating COPD, in a patient in need of such treatment (e.g., a mammal,preferably a human being) comprising administering to said patient atherapeutically effective amount of at least one (e.g., 1–3, and usuallyone) compound of formula IA, or a pharmaceutically acceptable salt orsolvate thereof.

Another embodiment of the present invention is directed to a method oftreating acute inflammation, in a patient in need of such treatment(e.g., a mammal, preferably a human being) comprising administering tosaid patient a therapeutically effective amount of at least one (e.g.,1–3, and usually one) compound of formula IA, or a pharmaceuticallyacceptable salt or solvate thereof.

Another embodiment of the present invention is directed to a method oftreating chronic inflammation, in a patient in need of such treatment(e.g., a mammal, preferably a human being) comprising administering tosaid patient a therapeutically effective amount of at least one (e.g.,1–3, and usually one) compound of formula IA, or a pharmaceuticallyacceptable salt or solvate thereof.

Another embodiment of the present invention is directed to a method oftreating rheumatoid arthritis, in a patient in need of such treatment(e.g., a mammal, preferably a human being) comprising administering tosaid patient a therapeutically effective amount of at least one (e.g.,1–3, and usually one) compound of formula IA, or a pharmaceuticallyacceptable salt or solvate thereof.

In another embodiment of the methods of this invention B is selectedfrom the group consisting of:

wherein all substituents are as defined for formula IA.

In another embodiment of the methods of this invention B is:

wherein:

R², R⁴, R⁵ and R⁶ are as defined for formula IA; and

R³ is selected from the group consisting of: hydrogen, cyano, halogen,alkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NHR¹⁷,—SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³OR⁴, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl, wherein thereare 1 to 6 substituents on said substituted aryl group and eachsubstituent is independently selected from the group consisting of: R⁹groups; and wherein there are 1 to 6 substituents on said substitutedheteroaryl group and each substituent is independently selected from thegroup consisting of: R⁹ groups.

In the methods of this invention:

(1) substituent A in formula IA is preferably selected from the groupconsisting of:

wherein the above rings are unsubstituted or substituted, as describedfor formula IA: and

wherein in (a) and (b) above: each R⁷ and R⁸ is independently selectedfrom the group consisting of: H, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

(2) substituent B in formula IA is preferably selected from the groupconsisting of:

wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above.

In the methods of this invention:

(1) substituent A in formula IA is more preferably selected from thegroup consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula IA, and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃,and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

(2) substituent B in formula IA is more preferably selected from thegroup consisting of:

wherein

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ or and—NHSO₂R¹³;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂, cyano,—C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃,halogen, and —CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano;

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

each R¹⁰ and R¹¹ is independently selected from the group consisting of:hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, and cyano;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl, isopropyl and t-butyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴,—CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom the group consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected fromthe group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹and —C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selectedfrom the group consisting of: alkyl, aryl and heteroaryl; wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., the substituents on the ring formed when R¹³ and R¹⁴ are takentogether with the nitrogen to which they are bound) and each substituentis independently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶is independently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

In the methods of this invention:

(1) substituent A in formula IA is even more preferably selected fromthe group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, fluoroalkyl, alkyl andcycloalkyl; R⁸ is selected form the group consisting of: H, alkyl,—CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F,Cl, Br, alkyl or —CF₃; and

wherein R⁷ is selected from the group consisting of: H, fluoroalkyl,alkyl and cycloalkyl; R⁸ is selected form the group consisting of: H,alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined for formula IA.

In the methods of this invention:

(1) substituent A in formula IA is still even more preferably selectedfrom the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA.

(2) substituent B in formula IA is preferably selected from the groupconsisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃ or—CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl, isopropyl and t-butyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴,—CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom O, S or NR¹⁸ wherein R¹⁸ is selected from H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰is independently selected from alkyl, aryl and heteroaryl, wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., on the ring formed when R¹³ and R¹⁴ are taken together with thenitrogen to which they are bound) and each substituent is independentlyselected from the group consisting of: alkyl, aryl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting of: H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

In the methods of this invention:

(1) substituent A in formula IA is yet even still more preferablyselected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA.

(2) substituent B in formula IA is preferably selected from the groupconsisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴,—NO₂, cyano, and —SO₂R¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃ or—CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:methyl and ethyl.

In the methods of this invention:

(1) substituent A in formula IA is most preferably selected from thegroup consisting of:

(2) substituent B in formula IA is preferably selected from the groupconsisting of:

wherein:

R² is —OH;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and —CONR¹³R¹⁴;

R⁴ is selected form the group consisting of: H, —CH₃ and —CF₃;

R⁵ is selected from the group consisting of: H and cyano;

R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

R¹¹ is H; and

R¹³ and R¹⁴ are methyl.

The novel compounds of this invention are compounds of formula IA:

and their pharmaceutically acceptable salts (e.g., sodium or calciumsalt) and solvates thereof, wherein:

A is selected from the group consisting of:

wherein the above rings of said A groups are substituted with 1 to 6substituents each independently selected from the group consisting of:R⁹ groups;

wherein one or both of the above rings of said A groups are substitutedwith 1 to 6 substituents each independently selected from the groupconsisting of: R⁹ groups;

wherein the above phenyl rings of said A groups are substituted with 1to 3 substituents each independently selected from the group consistingof: R⁹ groups; and

B is selected from the group consisting of:

provided that R³ for this group is selected from the group consistingof: —C(O)NR¹³R¹⁴,

n is 0 to 6;

p is 1 to 5;

X is O, NH, or S;

Z is 1 to 3;

R² is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH,—SO₂NR¹³R¹⁴, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —NR¹³R¹⁴,—C(O)NR¹³R¹⁴, —C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³, anunsubstituted heterocyclic acidic functional group, and a substitutedheterocyclic acidic functional group; wherein there are 1 to 6substituents on said substituted heterocyclic acidic functional groupeach substituent being independently selected from the group consistingof: R⁹ groups;

each R³ and R⁴ is independently selected from the group consisting of:hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂,—C(O)R¹³, —C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—SO_((t))R¹³, —C(O)NR¹³OR¹⁴, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl,

wherein there are 1 to 6 substituents on said substituted aryl group andeach substituent is independently selected from the group consisting of:R⁹ groups; andwherein there are 1 to 6 substituents on said substituted heteroarylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups;

each R⁵ and R⁶ are the same or different and are independently selectedfrom the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF₃,—OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NR ¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—C(O)NR¹³R¹⁴, cyano, unsubstituted or substituted aryl, andunsubstituted or substituted heteroaryl group; wherein there are 1 to 6substituents on said substituted aryl group and each substituent isindependently selected from the group consisting of: R⁹ groups; andwherein there are 1 to 6 substituents on said substituted heteroarylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups;

each R⁷ and R⁸ is independently selected from the group consisting of:H, unsubstituted or substituted alkyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, alkynyl, alkenyl, andcycloalkenyl; and wherein there are one or more (e.g., 1 to 6)substituents on said substituted R⁷ and R⁸ groups, wherein eachsubstituent is independently selected from the group consisting of:

-   -   a) halogen,    -   b) —CF₃,    -   c) —COR¹³,    -   d) —OR¹³,    -   e) —NR¹³R¹⁴,    -   f) —NO₂,    -   g) —CN,    -   h) —SO₂R¹³,    -   i) —Si(alkyl)₃, wherein each alkyl is independently selected,    -   j) —Si(aryl)₃, wherein each alkyl is independently selected,    -   k) —(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected,    -   l) —CO₂R¹³,    -   m) —C(O)NR¹³R¹⁴,    -   n) —SO₂NR¹³R¹⁴,    -   o) —SO₂R¹³,    -   p) —OC(O)R¹³,    -   q) —OC(O)NR¹³R¹⁴,    -   r) —NR¹³C(O)R¹⁴, and    -   s) —NR¹³CO₂R¹⁴;        (fluoroalkyl is one non-limiting example of an alkyl group that        is substituted with halogen);

R^(8a) is selected from the group consisting of: hydrogen, alkyl,cycloalkyl and cycloalkylalkyl;

each R⁹ is independently selected from the group consisting of:

-   -   a) —R¹³,    -   b) halogen,    -   c) —CF₃,    -   d) —COR¹³,    -   e) —OR¹³,    -   f) —NR¹³R¹⁴,    -   g) —NO₂,    -   h) —CN,    -   i) —SO₂R¹³,    -   j) —SO₂NR¹³R¹⁴,    -   k) —NR¹³COR¹⁴,    -   l) —CONR¹³R¹⁴,    -   m) —NR¹³CO₂R¹⁴,    -   n) —CO₂R¹³,

-   -   p) alkyl substituted with one or more (e.g., one) —OH groups        (e.g., —(CH₂)_(q)OH, wherein q is 1–6, usually 1 to 2, and        preferably 1),    -   q) alkyl substituted with one or more (e.g., one) —NR¹³R¹⁴ group        (e.g., —(CH₂)_(q)NR¹³R¹⁴, wherein q is 1–6, usually 1 to 2, and        preferably 1), and    -   r) —N(R¹³)SO₂R¹⁴ (e.g., R¹³ is H and R¹⁴ is alkyl, such as        methyl);

each R¹⁰ and R¹¹ is independently selected from the group consisting ofR¹³, hydrogen, alkyl (e.g., C₁ to C₆, such as methyl), halogen, —CF₃,—OCF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —OH, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³ and cyano;

R¹² is selected from the group consisting of: hydrogen, —C(O)OR¹³,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted cycloalkyl, unsubstituted or substituted alkyl,unsubstituted or substituted cycloalkylalkyl, and unsubstituted orsubstituted heteroarylalkyl group; wherein there are 1 to 6 substituentson the substituted R¹² groups and each substituent is independentlyselected from the group consisting of: R⁹ groups;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, unsubstituted or substituted alkyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, unsubstituted or substituted heterocyclic,unsubstituted or substituted fluoroalkyl, and unsubstituted orsubstituted heterocycloalkylalkyl (wherein “heterocyloalkyl” meansheterocyclic); wherein there are 1 to 6 substituents on said substitutedR¹³ and R¹⁴ groups and each substituent is independently selected fromthe group consisting of: alkyl, —CF₃, —OH, alkoxy, aryl, arylalkyl,fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,—N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, halogen, and —NHC(O)NR¹⁵R¹⁶; or

R¹³ and R¹⁴ taken together with the nitrogen they are attached to in thegroups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted or substitutedsaturated heterocyclic ring (preferably a 3 to 7 membered heterocyclicring), said ring optionally containing one additional heteroatomselected from the group consisting of: O, S and NR¹⁸; wherein there are1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., there is 1 to 3 substituents on the ring formed when the R¹³ andR¹⁴ groups are taken together with the nitrogen to which they are bound)and each substituent is independently selected from the group consistingof: alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and aheterocylcoalkenyl group (i.e., a heterocyclic group that has at leastone, and preferably one, double bond in a ring, e.g.,

each R¹⁵ and R¹⁶ is independently selected from the group consisting of:H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

R¹⁷ is selected from the group consisting of: —SO₂alkyl, —SO₂aryl,—SO₂cycloalkyl, and —SO₂heteroaryl;

R¹⁸ is selected from the group consisting of: H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰;

each R¹⁹ and R²⁰ is independently selected from the group consisting of:alkyl, aryl and heteroaryl;

R³⁰ is selected from the group consisting of: alkyl, cycloalkyl, —CN,—NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H;

each R³¹ is independently selected from the group consisting of:unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted cycloalkyl;wherein there are 1 to 6 substituents on said substituted R³¹ groups andeach substituent is independently selected from the group consisting of:alkyl, halogen, and —CF₃;

each R⁴⁰ is independently selected from the group consisting of: H,alkyl and cycloalkyl; and

t is 0, 1 or 2.

Representative embodiments of the novel compounds of this invention aredescribed below. The embodiments have been numbered for purposes ofreference thereto.

Embodiment No. 1 is directed to the novel compounds of formula IAwherein B is selected from the group consisting of:

provided that R³ for this group is selected from the group consistingof: —C(O)NR¹³R¹⁴,

wherein all substituents are as defined for the novel compounds offormula IA.

Embodiment No. 2 is directed to the novel compounds of formula IAwherein B is:

wherein R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴,

and all other substituents are as defined in formula IA.

Embodiment No. 3 is directed to the novel compounds of formula IAwherein B is:

and all other substituents are as defined in formula IA.

Embodiment No. 4 is directed to the novel compounds of formula IAwherein B is

R¹³ and R¹⁴ are each the same or different alkyl group, and all othersubstituents are as defined in formula IA.

Embodiment No. 5 is directed to the novel compounds of formula IAwherein B is

and (1) R² is —OH, and all other substituents are as defined in formulaIA, or (2) R² is —OH, and R¹³ and R¹⁴ are each the same or differentalkyl group, and all other substituents are as defined in formula IA.

Embodiment No. 6 is directed to the novel compounds of formula IAwherein B is

R³ is selected from the group consisting of:

and all other substituents are as defined in formula IA.

Embodiment No. 7 is directed to the novel compounds of formula IAwherein B is

R³ is selected from the group consisting of:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 8 is directed to compounds of formula IA wherein B is:

R², R¹³, and R¹⁴ are as defined for compounds of formula IA, and allother substituents are as defined in formula IA.

Embodiment No. 9 is directed to the novel compounds of formula IAwherein B is:

R² is —OH, R¹³ and R¹⁴ are as defined for compounds of formula and allother substituents are as defined in formula IA.

Embodiment No. 10 is directed to the novel compounds of formula IAwherein B is:

R² is as defined for compounds of formula IA, R¹³ and R¹⁴ are the sameor different alkyl group, and all other substituents areas defined forcompounds of formula IA.

Embodiment No. 11 is directed to the novel compounds of formula IAwherein B is:

R² is —OH, R¹³ and R¹⁴ are the same or different alkyl group, and allother substituents areas defined for compounds of formula IA.

Embodiment No. 12 is directed to novel compounds of formula IA wherein Bis as described in Embodiment No. 6, R⁴ is H, R⁵ is H, R⁶ is H, and allother substituents areas defined for compounds of formula IA.

Embodiment No. 13 is directed to novel compounds of formula IA wherein Bis as described in Embodiment No. 7, R⁴ is H, R⁵ is H, R⁶ is H, and allother substituents areas defined for compounds of formula IA.

Embodiment No. 14 is directed to novel compounds of formula IA wherein Bis as described in Embodiments Nos. 4, 5, 8 and 9, except that R¹³ andR¹⁴ are each methyl, and all other substituents are as defined informula IA.

Embodiment No. 15 is directed to novel compounds of formula IA wherein Bis selected from the group consisting of:

wherein all substituents are as defined for formula IA.

Embodiment No. 16 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 17 is directed to compounds of formula IA wherein B is:

R¹¹ is H, and all other substituents are as defined in formula IA.

Embodiment No. 18 is directed to compounds of formula IA wherein B is:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 19 is directed to compounds of formula IA wherein B is:

R³ is —C(O)NR¹³R¹⁴, and all other substituents are as defined in formulaIA.

Embodiment No. 20 is directed to compounds of formula IA wherein B is:

R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituents are asdefined in formula IA.

Embodiment No. 21 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, and all other substituents are as definedin formula IA.

Embodiment No. 22 of this invention is directed to compounds of formulaIA wherein B is:

R² is —OH, and R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all othersubstituents are as defined in formula IA.

Embodiment No. 23 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and all other substituents areas defined in formula IA.

Embodiment No. 24 is directed to compounds of formula IA wherein B is:

R³ is —S(O_(t)NR¹³R¹⁴ (e.g., t is 2), each R¹³ and R¹⁴ are the same ordifferent and are selected from the group consisting of: H and alkyl(e.g., methyl, ethyl, isopropyl and t-butyl). In this embodiment, eachR¹³ and R¹⁴ are generally selected from the group consisting of: H andethyl, and preferably R¹³ and R¹⁴ are ethyl, and all other substituentsare as defined in formula IA.

Embodiment No. 25 is directed to compounds of formula IA wherein B is:

R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, and each R¹³ and R¹⁴are the same or different and are selected from the group consisting of:H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl). In thisembodiment, each R¹³ and R¹⁴ are generally selected from the groupconsisting of: H and ethyl, and preferably R¹³ and R¹⁴ are ethyl, andall other substituents are as defined in formula IA.

Embodiment No. 26 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, and allother substituents are as defined in formula IA.

Embodiment No. 27 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and R¹³ and R¹⁴ areindependently selected from the group consisting of: alkyl,unsubstituted heteroaryl and substituted heteroaryl, and all othersubstituents are as defined in formula IA. In general, one of R¹³ or R¹⁴is alkyl (e.g., methyl). An example of a substituted heteroaryl group is

Embodiment No. 28 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, and each R¹³and R¹⁴ are the same or different and are selected from the groupconsisting of: H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl),and all other substituents are as defined in formula IA. In thisembodiment, each R¹³ and R¹⁴ are generally selected from the groupconsisting of: H and ethyl, and preferably R¹³ and R¹⁴ are ethyl.

Embodiment No. 29 is directed to compounds of formula IA wherein B is:

and all substituents are as defined in formula IA.

Embodiment No. 30 is directed to compounds of formula IA wherein B is:

and all substituents are as defined in formula IA.

Embodiment No. 31 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 30, and A is asdefined in any of the above preferred descriptions describing A for thecompounds of formula IA used in the methods of treatment.

Embodiment No. 32 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 30, and A is:

wherein the furan ring is unsubstituted or substituted as described inthe definition of A for formula IA, and all other substituents are asdefined for formula IA.

Embodiment No. 33 is directed to novel compounds of formula IA wherein Bis described in any one of the Embodiment Nos. 1 to 30, and A is

wherein the furan ring is substituted and all other substituents are asdefined for formula IA.

Embodiment No. 34 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 30, and A is

wherein the furan ring is substituted with at least one (e.g., 1 to 3,or 1 to 2) alkyl group and all other substituents are as defined forformula IA.

Embodiment No. 35 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 30, A is

wherein the furan ring is substituted with one alkyl group and all othersubstituents are as defined for formula IA.

Embodiment No. 36 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 30, and A is

wherein the furan ring is substituted with one C₁ to C₃ alkyl group(e.g., methyl or isopropyl), and all other substituents are as definedfor formula IA.

Embodiment No. 37 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 30, and A is

as defined in any one of the Embodiment Nos. 32 to 36, except that R⁷and R⁸ are the same or different and each is selected from the groupconsisting of: H and alkyl.

Embodiment No. 38 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 30, and A is

as defined in any one of the Embodiment Nos. 32 to 36, except that R⁷ isH, and R⁸ is alkyl (e.g., ethyl or t-butyl).

Embodiment No. 39 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is preferably selected from the groupconsisting of:

(a)

wherein the above rings are unsubstituted or substituted, as describedfor formula IA: and

and wherein in (a) and (b) above: each R⁷ and R⁸ is independentlyselected from the group consisting of: H, unsubstituted or substitutedalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

(2) substituent B in formula IA is preferably selected from the groupconsisting of:

wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above for the novelcompounds of formula IA.

Embodiment No. 40 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is more preferably selected from thegroup consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula IA, and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, is—OCH₃, and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

(2) substituent B in formula IA is more preferably selected from thegroup consisting of:

wherein

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂, cyano,—C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃,halogen, and —CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano;

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

each R¹⁰ and R¹¹ is independently selected from the group consisting of:R¹³, hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³,—SH, —SO_((t))NR¹³R ¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, and cyano;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl, isopropyl and t-butyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted orsubstituted saturated heterocyclic ring (preferably a 3 to 7 memberedring) optionally having one additional heteroatom selected from thegroup consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected from thegroup consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and—C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selected fromthe group consisting of: alkyl, aryl and heteroaryl; wherein there are 1to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e.,the substituents on the ring formed when R¹³ and R¹⁴ are taken togetherwith the nitrogen to which they are bound) and each substituent isindependently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶is independently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 41 is directed to the novel compounds of formula IAwherein:

substituent A in formula IA is even more preferably selected from the

substituent A in formula IA is even more preferably selected from the

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, fluoroalkyl, alkyl andcycloalkyl; R⁸ is selected form the group consisting of: H, alkyl,—CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F,Cl, Br, alkyl or —CF₃; and

wherein R⁷ is selected from the group consisting of: H, fluoroalkyl,alkyl and cycloalkyl; R⁸ is selected form the group consisting of: H,alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined for formula IA.

Embodiment No. 42 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is still even more preferably selectedfrom the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA.

(2) substituent B in formula IA is preferably selected from the groupconsisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R ¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

R⁴is selected from the group consisting of: H, —NO₂, cyano, —CH₃ or—CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl, isopropyl and t-butyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted orsubstituted saturated heterocyclic ring (preferably a 3 to 7 memberedring) optionally having one additional heteroatom selected from O, S orNR¹⁸ wherein R¹⁸ is selected from H, alkyl, aryl, heteroaryl, —C(O)R¹⁹,—SO₂R¹⁹ and —C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰ is independentlyselected from alkyl, aryl and heteroaryl, wherein there are 1 to 3substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e., onthe ring formed when R¹³ and R¹⁴ are taken together with the nitrogen towhich they are bound) and each substituent is independently selectedfrom the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting of: H. alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 43 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is yet even still more preferablyselected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA;

(2) substituent B in formula IA is yet even still more preferablyselected from the group consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴,—NO₂, cyano, and —SO₂R¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃ or—CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:methyl and ethyl.

Embodiment No. 44 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is most preferably selected from thegroup consisting of:

(2) substituent B in formula IA is most preferably selected from thegroup consisting of:

wherein:

R² is —OH;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and —CONR¹³R¹⁴;

R⁴ is selected form the group consisting of: H, —CH₃ and —CF₃;

R⁵ is selected from the group consisting of: H and cyano;

R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

R¹¹ is H; and

R¹³ and R¹⁴ are methyl.

Embodiment No. 45 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is selected from the group consistingof:

wherein the above rings are unsubstituted or substituted, as describedfor formula IA: and

wherein in (a) and (b) above: each R⁷ and R⁸ is independently selectedfrom the group consisting of: H, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

(2) substituent B in formula IA is:

wherein R², R³ and R¹¹ are as defined above for the novel compounds offormula IA.

Embodiment No. 46 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is selected from the group consistingof:

wherein the above rings are unsubstituted or substituted, as describedfor formula IA: and

wherein in (a) and (b) above: each R⁷ and R⁸ is independently selectedfrom the group consisting of: H, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

(2) substituent B in formula IA is:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂, cyano,—C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

R¹¹ is selected from the group consisting of: R¹³, hydrogen, halogen,—CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴,—SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —C(O)NR¹³R¹⁴,—C(O)NR¹³R¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, and cyano;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl, isopropyl and t-butyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴, form an unsubstituted orsubstituted saturated heterocyclic ring (preferably a 3 to 7 memberedring) optionally having one additional heteroatom selected from thegroup consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected from thegroup consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and—C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selected fromthe group consisting of: alkyl, aryl and heteroaryl; wherein there are 1to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups (i.e.,the substituents on the ring formed when R¹³ and R¹⁴ are taken togetherwith the nitrogen to which they are bound) and each substituent isindependently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶is independently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 47 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is selected from the group consistingof:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula IA, and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃,and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

(2) substituent B in formula IA is:

wherein

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ or and—NHSO₂R¹³;

R³ is —SO₂NR¹³R¹⁴;

R¹¹ is selected from the group consisting of: R¹³, hydrogen, halogen,—CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³, —SH, —SO_((t))NR¹³R¹⁴,—SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³, —C(O)NR¹³R¹⁴,—C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, and cyano;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl, isopropyl and t-butyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the group —SO₂NR¹³R¹⁴ form an unsubstituted or substituted saturatedheterocyclic ring (preferably a 3 to 7 membered ring) optionally havingone additional heteroatom selected from the group consisting of: O, S orNR¹⁸; wherein R¹⁸ is selected from the group consisting of: H, alkyl,aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰; wherein each R¹⁹and R²⁰ is independently selected from the group consisting of: alkyl,aryl and heteroaryl; wherein there are 1 to 3 substituents on thesubstituted cyclized R¹³ and R¹⁴ groups (i.e., the substituents on thering formed when R¹³ and R¹⁴ are taken together with the nitrogen towhich they are bound) and each substituent is independently selectedfrom the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 48 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is selected from the group consistingof:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA.

(2) substituent B in formula IA is:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl, isopropyl and t-butyl.

Embodiment No. 43 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is selected from the group consistingof:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA;

(2) substituent B in formula IA is:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³ (preferably —OH);

R³ is —SO₂NR¹³R¹⁴;

R¹¹ is selected from the group consisting of: H, halogen and alkyl(preferably H); and

each R¹³ and R¹⁴ is independently selected from the group consisting of:H and ethyl, preferably R¹³ and R¹⁴ are ethyl.

Embodiment No. 50 is directed to the novel compounds of formula IAwherein:

(1) substituent A in formula IA is selected from the group consistingof:

(2) substituent B in formula IA is:

wherein:

R² is —OH;

R³ is: —SO₂NR¹³R¹⁴;

R¹¹ is H; and

R¹³ and R¹⁴ are ethyl.

Embodiment No. 51 is directed to compounds of formula IA wherein B isselected from the group consisting of:

provided that R³ for this group is selected from the group consistingof: —C(O)NR¹³R¹⁴,

wherein all other substituents are as defined for formula IA.

Embodiment No. 52 is directed to compounds of formula IA wherein B isselected from the group consisting of:

wherein all substituents are as defined for formula IA.

Embodiment No. 53 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 54 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 55 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 56 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 57 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 58 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 59 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 60 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 61 is directed to compounds of formula IA wherein B is:

wherein all substituents are as defined for formula IA.

Embodiment No. 62 is directed to compounds of formula IA wherein B isselected from the group consisting of:

wherein all substituents are as defined for formula IA.

Embodiment No. 63 is directed to compounds of formula IA wherein B isdescribed in any of Embodiment Nos. 51 to 62 and A is as described inany of Embodiments Nos. 31–44.

Embodiment No. 64 is directed to any one of the Embodiment Nos. 1 to 63wherein the novel compound of formula IA is a pharmaceuticallyacceptable salt.

Embodiment No. 65 is directed to any one of the Embodiment Nos. 1 to 63wherein the novel compound of formula IA is a sodium salt.

Embodiment No. 66 is directed to any one of the Embodiment Nos. 1 to 63wherein the novel compound of formula IA is a calcium salt.

Embodiment No. 67 is directed to a pharmaceutically acceptable salt ofany one of the representative novel compounds described below.

Embodiment No. 68 is directed to a sodium salt of any one of therepresentative novel compounds described below.

Embodiment No. 69 is directed to a calcium salt of any one of therepresentative novel compounds described below.

Embodiment No. 70 is directed to a pharmaceutical composition comprisingat least one (e.g., 1 to 3, usually 1) novel compound of formula IA asdescribed in any one of the Embodiment Nos. 1 to 69 in combination witha pharmaceutically acceptable carrier (or diluent).

Embodiment No. 71 is directed to a method of treating any one of thediseases described herein (e.g., the chemokine mediated diseases, andcancer) comprising administering to a patient in need of such treatmentan effective amount (e.g., a therapeutically effective amount) of anovel compound of formula IA as described in any one of the EmbodimentNos. 1 to 69.

Embodiment No. 72 is directed to novel compounds of Examples 2006, 2010,2015, 2029, 2034, 2035, 2038, 2039, 2047, 2050, 2074, 2079, and 2087.

Embodiment No. 73 is directed to a pharmaceutical composition comprisingat least one (e.g., 1 to 3, usually 1) novel compound of Embodiment No.72 (or a pharmaceutically acceptable salt or solvate thereof, e.g., acalcium or sodium salt) in combination with a pharmaceuticallyacceptable carrier (or diluent).

Embodiment No. 74 is directed to a method of treating any one of thediseases described herein (e.g., the chemokine mediated diseases, andcancer) comprising administering to a patient in need of such treatmentan effective amount (e.g., a therapeutically effective amount) of atleast one (e.g., 1 to 3, usually 1) compound of

Embodiment No. 72 (or a pharmaceutically acceptable salt or solvatethereof, e.g., a calcium or sodium salt).

Representative compounds of the invention include but are not limitedto:

Preferred compounds of the invention include:

A more preferred group of compounds includes:

A most preferred group of compounds includes:

Certain compounds of the invention may exist in different stereoisomericforms (e.g., enantiomers, diastereoisomers and atropisomers). Theinvention contemplates all such stereoisomers both in pure form and inadmixture, including racemic mixtures. Isomers can be prepared usingconventional methods.

Certain compounds will be acidic in nature, e.g. those compounds whichpossess a carboxyl or phenolic hydroxyl group. These compounds may formpharmaceutically acceptable salts. Examples of such salts may includesodium, potassium, calcium, aluminum, gold and silver salts. Alsocontemplated are salts formed with pharmaceutically acceptable aminessuch as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine andthe like.

Certain basic compounds also form pharmaceutically acceptable salts,e.g., acid addition salts. For example, the pyrido-nitrogen atoms mayform salts with strong acid, while compounds having basic substituentssuch as amino groups also form salts with weaker acids. Examples ofsuitable acids for salt formation are hydrochloric, sulfuric,phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric,succinic, ascorbic, maleic, methanesulfonic and other mineral andcarboxylic acids well known to those skilled in the art. The salts areprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt in the conventional manner. The freebase forms may be regenerated by treating the salt with a suitabledilute aqueous base solution such as dilute aqueous NaOH, potassiumcarbonate, ammonia and sodium bicarbonate. The free base forms differfrom their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise equivalent to their respective free base forms forpurposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of formula IA can exist in unsolvated and solvated forms,including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for the purposes of thisinvention.

In a preferred embodiment of the treatment of cancer, a compound offormula IA is administered in combination with one of the followingantineoplastic agents: gemcitabine, paclitaxel (Taxol®), 5-Fluorourcil(5-FU), cyclophosphamide (Cytoxan®), temozolomide, or Vincristine.

In another preferred embodiment, the present invention provides a methodof treating cancer, comprising administering, concurrently orsequentially, and effective amount of a compound of formula IA and amicrotubule affecting agent e.g., paclitaxel.

Another embodiment of the invention is directed to a method treatingcancer, comprising administering to a patient in need thereof,concurrently or sequentially, a therapeutically effective amount of (a)a compound of formula IA, and (b) an antineoplastic agent, microtubuleaffecting agent or anti-angiogenesis agent.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal composition can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.01 mg to about 1000 mg, preferably fromabout 0.01 mg to about 750 mg, more preferably from about 0.01 mg toabout 500 mg, and most preferably from about 0.01 mg to about 250 mg,according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total dosage may bedivided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.04mg/day to about 4000 mg/day, in two to four divided doses.

Classes of compounds that can be used as the chemotherapeutic agent(antineoplastic agent) include: alkylating agents, antimetabolites,natural products and their derivatives, hormones and steroids (includingsynthetic analogs), and synthetics. Examples of compounds within theseclasses are given below.

Alkylating agents (including nitrogen mustards, ethyleniminederivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracilmustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, and Temozolomide.

Antimetabolites (including folic acid antagonists, pyrimidine analogs,purine analogs and adenosine deaminase inhibitors): Methotrexate,5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

Natural products and their derivatives (including vinca alkaloids,antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins):Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel(paclitaxel is commercially available as Taxol® and is described in moredetail below in the subsection entitled “Microtubule Affecting Agents”),Mithramycin, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons(especially IFN-a), Etoposide, and Teniposide.

Hormones and steroids (including synthetic analogs):17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, Zoladex.

Synthetics (including inorganic complexes such as platinum coordinationcomplexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, andHexamethylmelamine.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g., 2002edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA); thedisclosure of which is incorporated herein by reference thereto.

As used herein, a microtubule affecting agent is a compound thatinterferes with cellular mitosis, i.e., having an anti-mitotic effect,by affecting microtubule formation and/or action. Such agents can be,for instance, microtubule stabilizing agents or agents that disruptmicrotubule formation.

Microtubule affecting agents useful in the invention are well known tothose of skill in the art and include, but are not limited toallocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine(NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel(Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives (e.g., NSC608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265),vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574),epothilone A, epothilone, and discodermolide (see Service, (1996)Science, 274:2009) estramustine, nocodazole, MAP4, and the like.Examples of such agents are also described in the scientific and patentliterature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055–3064; Panda(1997) Proc. Natl. Acad. Sci. USA 94:10560–10564; Muhlradt (1997) CancerRes. 57:3344–3346; Nicolaou (1997) Nature 387:268–272; Vasquez (1997)Mol. Biol. Cell. 8:973–985; Panda (1996) J. Biol. Chem. 271:29807–29812.

Particularly preferred agents are compounds with paclitaxel-likeactivity. These include, but are not limited to paclitaxel andpaclitaxel derivatives (paclitaxel-like compounds) and analogues.Paclitaxel and its derivatives are available commercially. In addition,methods of making paclitaxel and paclitaxel derivatives and analoguesare well known to those of skill in the art (see, e.g., U.S. Pat. Nos.5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589;5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769;5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506).

More specifically, the term “paclitaxel” as used herein refers to thedrug commercially available as Taxol® (NSC number: 125973). Taxol®inhibits eukaryotic cell replication by enhancing polymerization oftubulin moieties into stabilized microtubule bundles that are unable toreorganize into the proper structures for mitosis. Of the many availablechemotherapeutic drugs, paclitaxel has generated interest because of itsefficacy in clinical trials against drug-refractory tumors, includingovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17–23,Horwitz (1992) Trends Pharmacol. Sci. 13: 134–146, Rowinsky (1990) J.Natl. Canc. Inst. 82: 1247–1259).

Additional microtubule affecting agents can be assessed using one ofmany such assays known in the art, e.g., a semiautomated assay whichmeasures the tubulin-polymerizing activity of paclitaxel analogs incombination with a cellular assay to measure the potential of thesecompounds to block cells in mitosis (see Lopes (1997) Cancer Chemother.Pharmacol. 41:37–47).

Generally, activity of a test compound is determined by contacting acell with that compound and determining whether or not the cell cycle isdisrupted, in particular, through the inhibition of a mitotic event.Such inhibition may be mediated by disruption of the mitotic apparatus,e.g., disruption of normal spindle formation. Cells in which mitosis isinterrupted may be characterized by altered morphology (e.g.,microtubule compaction, increased chromosome number, etc.).

Compounds with possible tubulin polymerization activity can be screenedin vitro. In a preferred embodiment, the compounds are screened againstcultured WR21 cells (derived from line 69-2 wap-ras mice) for inhibitionof proliferation and/or for altered cellular morphology, in particularfor microtubule compaction. In vivo screening of positive-testingcompounds can then be performed using nude mice bearing the WR21 tumorcells. Detailed protocols for this screening method are described byPorter (1995) Lab. Anim. Sci., 45(2):145–150.

Other methods of screening compounds for desired activity are well knownto those of skill in the art. Typically such assays involve assays forinhibition of microtubule assembly and/or disassembly. Assays formicrotubule assembly are described, for example, by Gaskin et al. (1974)J. Molec. Biol., 89: 737–758. U.S. Pat. No. 5,569,720 also provides invitro and in vivo assays for compounds with paclitaxel-like activity.

Methods for the safe and effective administration of the above-mentionedmicrotubule affecting agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g., 1996edition (Medical Economics Company, Montvale, N.J. 07645–1742, USA); thedisclosure of which is incorporated herein by reference thereto.

The amount and frequency of administration of the compounds of formulaIA and the chemotherapeutic agents and/or radiation therapy will beregulated according to the judgment of the attending clinician(physician) considering such factors as age, condition and size of thepatient as well as severity of the disease being treated. A dosageregimen of the compound of formula IA can be oral administration of from10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50to 600 mg/day, in two to four (preferably two) divided doses, to blocktumor growth. Intermittant therapy (e.g., one week out of three weeks orthree out of four weeks) may also be used.

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents.

In the methods of this invention, a compound of formula IA isadministered concurrently or sequentially with a chemotherapeutic agentand/or radiation. Thus, it is not necessary that, for example, thechemotherapeutic agent and the compound of formula IA, or the radiationand the compound of formula IA, should be administered simultaneously oressentially simultaneously. The advantage of a simultaneous oressentially simultaneous administration is well within the determinationof the skilled clinician.

Also, in general, the compound of formula IA and the chemotherapeuticagent do not have to be administered in the same pharmaceuticalcomposition, and may, because of different physical and chemicalcharacteristics, have to be administered by different routes. Forexample, the compound of formula IA may be administered orally togenerate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

The particular choice of a compound of formula IA, and chemo-therapeuticagent and/or radiation will depend upon the diagnosis of the attendingphysicians and their judgement of the condition of the patient and theappropriate treatment protocol.

The compound of formula IA, and chemotherapeutic agent and/or radiationmay be administered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the proliferative disease, the condition ofthe patient, and the actual choice of chemotherapeutic agent and/orradiation to be administered in conjunction (i.e., within a singletreatment protocol) with the compound of formula or IA.

If the compound of formula IA, and the chemotherapeutic agent and/orradiation are not administered simultaneously or essentiallysimultaneously, then the initial order of administration of the compoundof formula IA, and the chemotherapeutic agent and/or radiation, may notbe important. Thus, the compound of formula IA may be administeredfirst, followed by the administration of the chemotherapeutic agentand/or radiation; or the chemotherapeutic agent and/or radiation may beadministered first, followed by the administration of the compound offormula IA. This alternate administration may be repeated during asingle treatment protocol. The determination of the order ofadministration, and the number of repetitions of administration of eachtherapeutic agent during a treatment protocol, is well within theknowledge of the skilled physician after evaluation of the disease beingtreated and the condition of the patient.

For example, the chemotherapeutic agent and/or radiation may beadministered first, especially if it is a cytotoxic agent, and then thetreatment continued with the administration of the compound of formulaIA followed, where determined advantageous, by the administration of thechemotherapeutic agent and/or radiation, and so on until the treatmentprotocol is complete.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a component(therapeutic agent—i.e., the compound of formula IA, chemotherapeuticagent or radiation) of the treatment according to the individualpatient's needs, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thepatient as well as more definite signs such as relief of disease-relatedsymptoms, inhibition of tumor growth, actual shrinkage of the tumor, orinhibition of metastasis. Size of the tumor can be measured by standardmethods such as radio-logical studies, e.g., CAT or MRI scan, andsuccessive measurements can be used to judge whether or not growth ofthe tumor has been retarded or even reversed. Relief of disease-relatedsymptoms such as pain, and improvement in overall condition can also beused to help judge effectiveness of treatment.

BIOLOGICAL EXAMPLES

The compounds of the present invention are useful in the treatment ofCXC-chemokine mediated conditions and diseases. This utility ismanifested in their ability to inhibit IL-8 and GRO-α chemokine asdemonstrated by the following in vitro assays.

Receptor Binding Assays:

CXCR1 SPA Assay

For each well of a 96 well plate, a reaction mixture of 10 μg hCXCR1-CHOoverexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads(Amersham) in 100 μl was prepared in CXCR1 assay buffer (25 mM HEPES, pH7.8, 2 mM CaCl₂, 1 mM MgCl₂, 125 mM NaCl, 0.1% BSA) (Sigma). A 0.4 nMstock of ligand, [125I]-IL-8 (NEN) was prepared in the CXCR1 assaybuffer. 20× stock solutions of test compounds were prepared in DMSO(Sigma). A 6× stock solution of IL-8 (R&D) was prepared in CXCR2 assaybuffer. The above solutions were added to a 96-well assay plate(PerkinElmer) as follows: 10 μl test compound or DMSO, 40 μl CXCR1 assaybuffer or IL-8 stock, 100 μl of reaction mixture, 50 μl of ligand stock(Final [Ligand]=0.1 nM). The assay plates were shaken for 5 minutes onplate shaker, then incubated for 8 hours before cpm/well were determinedin Microbeta Trilux counter (PerkinElmer). % Inhibition of Totalbinding-NSB (250 nM IL-8) was determined for IC50 values. Compounds ofthis invention had an IC₅₀ of <20 μM. The most preferred compounds had aK_(i) within the range of 3 nM to 1120 nM.

CXCR2 SPA Assay

For each well of a 96 well plate, a reaction mixture of 4 μg hCXCR2-CHOoverexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads(Amersham) in 100 μl was prepared in CXCR2 assay buffer (25 mM HEPES, pH7.4, 2 mM CaCl₂, 1 mM MgCl₂). A 0.4 nM stock of ligand, [125I]-IL-8(NEN), was prepared in the CXCR2 assay buffer. 20× stock solutions oftest compounds were prepared in DMSO (Sigma). A 6× stock solution ofGRO-α (R&D) was prepared in CXCR2 assay buffer. The above solutions wereadded to a 96-well assay plate (PerkinElmer or Corning) as follows: 10μl test compound or DMSO, 40 ul CXCR2 assay buffer or GRO-α stock, 100μl of reaction mixture, 50 μl of ligand stock (Final [Ligand]=0.1 nM).When 40× stock solutions of test compounds in DMSO were prepared, thenthe above protocol was used except instead 5 μl test compound or DMSOand 45 μl CXCR2 assay buffer were used. The assay plates were shaken for5 minutes on a plate shaker, then incubated for 2–8 hours beforecpm/well were determined in Microbeta Trilux counter (PerkinElmer). %Inhibition of total binding minus non-specific binding (250 nM Gro-α or50 μM antagonist) was determined and IC50 values calculated. Compoundsof this invention had an IC₅₀ of <5 μM. The most preferred compounds hada K_(i) within the range of 0.8 nM to 40 nM. The compound of Example360.31 had a K_(i) of 3 nM. The compound of Example 360.106 had a K_(i)of 0.8 nM.

Calcium Fluorescence Assay (FLIPR)

HEK 293 cells stably transfected with hCXCR2 and Gαι/q were plated at10,000 cells per well in a Poly-D-Lysine Black/Clear plate (BectonDickinson) and incubated 48 hours at 5% CO₂, 37° C. The cultures werethen incubated with 4 mM fluo-4, AM (Molecular Probes) in Dye LoadingBuffer (1% FBS, HBSS w. Ca & Mg, 20 mM HEPES (Cellgro), 2.5 mMProbenicid (Sigma) for 1 hour. The cultures were washed with wash buffer(HBSS w Ca, & Mg, 20 mM HEPES, Probenicid (2.5 mM)) three times, then100 μl/well wash buffer was added.

During incubation, compounds were prepared as 4× stocks in 0.4% DMSO(Sigma) and wash buffer and added to their respective wells in the firstaddition plate. IL-8 or GRO-α (R&D Systems) concentrations were prepared4× in wash buffer+0.1% BSA and added to their respective wells in secondaddition plate.

Culture plate and both addition plates were then placed in the FLIPRimaging system to determine change in calcium fluorescence upon additionof compound and then ligand. Briefly, 50 μl of compound solutions orDMSO solution was added to respective wells and change in calciumfluorescence measured by the FLIPR for 1 minute. After a 3 minuteincubation within the instrument, 50 μl of ligand was then added and thechange in calcium fluorescence measured by the FLIPR instrument for 1minute. The area under each stimulation curve was determined and valuesused to determine % Stimulation by compound (agonist) and % Inhibitionof Total Calcium response to ligand (0.3 nM IL-8 or GRO-α) for IC50values of the test compounds.

Chemotaxis Assays for 293-CXCR2

A chemotaxis assay is setup using Fluorblok inserts (Falcon) for293-CXCR2 cells (HEK-293 cells overexpressing human CXCR2). The standardprotocol used at present is as follows:

-   1. Inserts are coated with collagenIV (2 ug/ml) for 2 hrs at 37° C.-   2. The collagen is removed and inserts are allowed to air dry    overnight.-   3. Cells are labeled with 10 uM calcein AM (Molecular Probes) for 2    hrs. Labeling is done in complete media with 2% FBS.-   4. Dilutions of compound are made in minimal media (0.1% BSA) and    placed inside the insert which is positioned inside the well of a 24    well plate. Within the well is IL-8 at a concentration of 0.25 nM in    minimal media. Cells are washed and resuspended in minimal media and    placed inside the insert at a concentration of 50,000 cells per    insert.-   5. Plate is incubated for 2 hrs and inserts are removed and placed    in a new 24 well. Fluorescence is detected at excitation=485 nM and    emission=530 nM.    Cytotoxicity Assays

A cytotoxicity assay for CXCR2 compounds is conducted on 293-CXCR2cells. Concentrations of compounds are tested for toxicity at highconcentrations to determine if they may be used for further evaluationin binding and cell based assays. The protocol is as follows:

-   1. 293-CXCR2 cells are plated overnight at a concentration of 5000    cells per well in complete media.-   2. Dilutions of compound are made in minimal media w/0.1% BSA.    Complete media is poured off and the dilutions of compound are    added. Plates are incubated for 4, 24 and 48 hrs. Cells are labeled    with 10 uM calcein AM for 15 minutes to determine cell viability.    Detection method is the same as above.    Soft Agar Assay

10,000 SKMEL-5 cells/well are placed in a mixture of 1.2% agar andcomplete media with various dilutions of compound. Final concentrationof agar is 0.6%. After 21 days viable cell colonies are stained with asolution of MTT (1 mg/ml in PBS). Plates are then scanned to determinecolony number and size. IC₅₀ is determined by comparing total area vs.compound concentration.

Compounds of formula IA may be produced by processes known to thoseskilled in the art, in the following reaction schemes, and in thepreparations and examples below.

A general procedure for the preparation of compounds of formula IA is asfollows:

Scheme 1

An amine is condensed (Step A) with a nitrosalicylic acid under standardcoupling conditions and the resulting nitrobenzamide is reduced (Step B)under hydrogen atmosphere in the presence of a suitable catalyst. Theremaining partner required for the synthesis of the final target isprepared by condensing an aryl amine with the commercially availablediethylsquarate to give the aminoethoxysquarate product. Subsequentcondensation of this intermediate with the aminobenzamide preparedearlier provides the desired chemokine antagonist (Scheme 1).

Scheme 2

Alternatively, the aminobenzamide of Scheme 1 is first condensed withcommercially available diethylsquarate to give an alternate monoethoxyintermediate. Condensation of this intermediate with an amine gives thedesired chemokine antagonist.

Scheme 3

Benztriazole compounds of Formula (I) or IA are prepared by stirringnitrophenylenediamines with sodium nitrite in acetic acid at 60° C. toafford the nitrobenzotriazole intermediate (Scheme 3). Reduction of thenitro group in the presence of palladium catalyst and hydrogenatmosphere provides the amine compound. Subsequent condensation of thisintermediate with the aminooethoxysquarate prepared earlier (Scheme 1)provides the desired chemokine antagonist.

Scheme 4

Condensation of nitrophenylenediamines with anhydrides or activatedacids at reflux (Scheme 4) affords benzimidazole intermediates whichafter reduction with hydrogen gas and palladium catalyst andcondensation with the aminoethoxysquarate previously prepared (Scheme 1)affords benzimidazole chemokine antagonists.

Scheme 5

Indazole structures of Formula (I) or IA can be prepared according toScheme 5 by reduction of nitroindazole A (J. Am. Chem Soc. 1943, 65,1804–1805) to give aminoindazole B and subsequent condensation with theaminoethoxysquarate prepared earlier (Scheme 1).

Scheme 6

Indole structures of Formula (I) or IA can be prepared according toScheme 6 by reduction of nitroindole A (J. Med. Chem. 1995, 38,1942–1954) to give aminoindole B and subsequent condensation with theaminoethoxysquarate prepared earlier (Scheme 1).

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures may be apparent to those skilled in the art.

Preparative Example 1

3-Nitrosalicylic acid (500 mg, 2.7 mmol), DCC (563 mg) and ethyl acetate(10 mL) were combined and stirred for 10 min.(R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and the resultingsuspension was stirred at room temperature overnight. The solid wasfiltered and the filtrate washed with 1N NaOH. The aqueous phase wasacidified and extracted with EtOAc. The resulting organic phase wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the residue by preparative plate chromatography (silicagel, 5% MeOH/CH₂Cl₂ saturated with AcOH) gave the product (338 mg, 46%,MH⁺=267).

Preparative Example 2

Step A

3-Nitrosalicylic acid (9.2 g), bromotripyrrolidinophosphoniumhexafluorophosphate (PyBroP, 23 g) and N,N-diisopropylethylamine (DIEA,26 mL) in anhydrous CH₂Cl₂ (125 mL) were combined and stirred at 25° C.for 30 min. (R)-(+)-3-pyrrolidinol (8.7 g) in CH₂Cl₂ (25 mL) was addedover 25 min and the resulting suspension was stirred at room temperatureovernight. The mixture was extracted with 1M NaOH (aq) and the organicphase was discarded. The aqueous phase was acidified with 1M HCl (aq),extracted with EtOAc, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the crude product (7 g) which was usedwithout further purification.

Step B

The crude product from Step A above was stirred with 10% Pd/C (0.7 g) inMeOH (100 mL) under a hydrogen gas atmosphere overnight. The reactionmixture was filtered through celite, the filtrate concentrated in vacuo,and the resulting residue purified by column chromatography (silica gel,10% MeOH/CH₂Cl₂ saturated with NH₄OH) to give the product (2.5 g, 41%,MH+=223).

Preparative Example 2.1

To N-BOC-3-(amino)piperidine (0.5 g) dissolved in CH₂Cl₂ (10 mL) wasadded benzylisocyanate (3 mmol). After stirring for 2 hrs, aminescavenger resin (1.9 mmol) was added and the mixture was stirredovernight, filtered, the resin back-washed with CH₂Cl₂ and methanol, andthe organics concentrated in vacuo. Stirring of the crude material in 4NHCl/dioxane (40 mL) for 2.5 hrs before concentrating in vacuo gave thetitle compound (41%, MH+=369).

Preparative Example 2.2–2.6

Following the procedures set forth in Preparative Example 2.1 but usingthe isocyanate (or chloroformate) indicated in the Table below, theamines were obtained and used without further purification.

Prep Ex. Amine Isocyanate Amine 2.2

2.3

2.4

2.5

2.6

Preparative Example 2.7

To N-BOC-3-(amino)piperidine (5 mmol) dissolved in CH₂Cl₂ (30 mL) wasadded trifluoromethanesulfonic anhydride (5 mmol) and the mixture wasstirred overnight. The mixture was concentrated in vacuo, diluted withCH₂Cl₂ (10 mL) and treated with trifluoroacetic acid (10 mL). Afterstirring for 2 hr, the mixture was concentrated in vacuo to give thetitle compound (43%, MH+=233.1).

Preparative Example 2.8

Step A

3-Nitrosalicylic acid (5 mmol) and N-hydroxysuccinimide (5 mmol) wereadded to a solution of 2% DMF/CH₂Cl₂, followed by DCC (5 mmol). Afterstirring for 2 hr, the mixture was filtered and concentrated in vacuoand the residue used directly in Step B.

Step B

The product from Step A above was suspended in DMF and to this was addedmorpholino-2-carboxylic acid HCl (5 mmol) in CH₂Cl₂ (10 mL)/DMF (5 mL)and diisopropylethylamine (10 mmol). The mixture was stirred overnight,filtered, basified with 1N NaOH (50 mL), washed with CH₂Cl₂, acidifiedwith 5N HCl and extracted with EtOAc. The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo to give the desired compoundwhich was used directly in Step C (MH+=296).

Step C

Following a similar procedure as in Preparative Example 2 Step B, butusing the product from Step B above, the title compound was obtained(23%, MH+=267).

Preparative Example 2.9

Step A

2-Piperazinecarboxylic acid and 2-chloro-1,3-pyrimidine were stirredwith triethylamine and MeOH. After stirring overnight at reflux, themixture was filtered and concentrated in vacuo to give the desiredcompound which was used directly in Step B (MH+=209).

Step B

Following a similar procedure as Preparative Example 2.8, Step B exceptusing the product from Preparative Example 2.9 Step A above, the desiredcompound was obtained (41%, MH+=374).

Step C

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step B above, the desired compound was obtained(99%, MH+=344).

Preparative Example 2.10

Step A

Following a similar procedure as Preparative Example 2.8, Step A exceptusing 3-nitrobenzoic acid, the desired compound was obtained and useddirectly in Step B.

Step B

Following a similar procedure as Preparative Example 2.8, Step B exceptusing the products from Preparative Example 2.9, Step A and PreparativeExample 2.10, Step A, the desired compound was obtained (86%).

Step C

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step B above, the desired compound was obtained(67%, MH+=331).

Preparative Example 2.11

Step A

N-Benzylpiperidone (2 g, HCl salt, hydrate) was stirred with THF (20mL), concentrated to dryness, and placed under high vac. The residue wasdiluted in THF (20 mL), and methyllithium was added (2.5 eq of 1.6N inEt₂O) via syringe. After stirring for 3 hr, the mixture was concentratedin vacuo, diluted with water, extracted with CH₂Cl₂, and dried overNa₂SO₄. Filtration and concentrating in vacuo gave the desired product(50%, MH+=205).

Step B

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step A above, the title compound was obtained(95%, MH+=116).

Preparative Example 2.12

Step A

To N-benzyl-N-methylamine (20 mmol) dissolved in acetone (50 mL) wasadded concentrated HCl (20 mmol), paraformaldehyde (30 mmol) and2-propanol (2 mL). After stirring at reflux overnight, the mixture wasconcentrated in vacuo, diluted with water, basified to pH 14 andextracted with ether. The organic phase was dried over Na₂SO₄, filteredand concentrated in vacuo to give the desired product (98%) which wasused directly in Step B.

Step B

The product from Step A above (500 mg) was dissolved in MeOH (20 mL) andto this was added NaBH₄ (50 mg). After stirring for 10 min, the solutionwas concentrated in vacuo to give the desired compound which was useddirectly in Step C without purification.

Step C

The product from Step B above was diluted with MeOH (20 mL) and to thiswas added AcOH (0.1 mL), a catalytic amount of Pd/C (10%) and themixture stirred under H₂ atmosphere (balloon) overnight. The mixture wasfiltered, 4N HCl in dioxane (1 mL) was added, and the mixture wasconcentrated in vacuo to give the desired compound that was useddirectly without purification.

Preparative Example 2.13

Step A

Following a similar procedure as Preparative Example 2, Step A exceptusing methyl glycinate, the desired ester was obtained. The mixture waspoured into 200 mL of 1N NaOH, then extracted with dichloromethane. ThepH was adjusted to 1 and NaCl was added until saturation. After severalhours, the resulting precipitate was filtered and washed with cold waterto give the desired product (42%).

Step B

Following a similar procedure as in Preparative Example 2 Step B, butusing the product from Step A above, the title compound was obtained(95%).

Preparative Example 2.14

Step A

Following a similar procedure as in Preparative Example 2.13, Step Aexcept using methyl N-methylglycinate, the desired product was obtained(18%).

Step B

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step A above, the title compound was obtained(95%, MH+=225).

Preparative Example 2.15

The cyclobutenedione intermediate from Preparative Example 87 (200 mg),DIEA (100 ul), 3-aminosalicylic acid (120 mg) and EtOH (4 ml) werecombined and heated to reflux overnight to give the title compound (90%,MH+=367).

Preparative Example 2.16

The above n-oxide (2 g) was combined with H₂NMe/H₂O (15 cm³) and heatedto 140° C. overnight. Potassium carbonate (1.3 g) added and the mixtureconcentrated in vacuo. Extraction with EtOH and concentration of thefiltrate in vacuo gave 1.56 g of crude amine (MH+=125).

Preparative Example 3–10.50

Following the procedures set forth in Preparative Examples 1–2 but usingthe carboxylic acid, amine, and coupling agent [DCC (Prep. Ex. 1) orPyBrop (Prep. Ex. 2)] listed in the Table below, the indicated amideproducts were obtained and used without further purification.

1. Coupling Agent Prep Carboxylic 2. % Yield Ex. acid Amine Product 3.MH⁺  3

1. PyBrop2. 87%, 86%3. 181  4

1. PyBroP2. 49%3. 209  5

NH₃

1. PyBroP2. 95%3. 153  6

1. PyBroP2. 83%3. 167  7

1. PyBroP2. 76%3. 223  8

1. PyBroP2. 65, 533. 209  9

1. PyBroP2. 59, 693. 207 10

1. PyBroP2. 49, 863. 237 10.1

1. PyBroP2. 30, 883. 193 10.2

1. PyBroP2. 26, 873. 195 10.3

1. PyBroP2. 383. 209 10.4

1. PyBroP2. 293. 209 10.5

1. PyBroP2. 383. 223 10.6

1. PyBroP2. 32, 993. 367.9 10.7

1. PyBroP2. 35, 993. 237 10.8

1. DCC2. 30, 993. 269 10.9

1. PyBroP2. 58, 953. 233.1 10.10

1. PyBroP2. 42, 953. 238.9 10.13

1. PyBroP2. 51, 953. 307 10.14

1. PyBroP2. 553. 347 10.15

1. PyBroP2. 413. 369.1 10.16

1. PyBroP2. 563. 354.9 10.17

1. PyBroP2. 563. 308 10.18

1. PyBroP2. 10, 953. 252.9 10.19

1. PyBroP2. 42, 953. 249 10.20

1. PyBroP2. 15, 953. 264.9 10.21

1. PyBroP2. 64, 953. 273 10.22

1. PyBroP2. 45, 953. 273 10.23

1. PyBroP2. 44, 953. 281 10.24

1. PyBroP2. 41, 953. 281.1 10.25

1. PyBroP2. 48, 953. 257 10.26

1. DCC2. 15, 993. 235 10.28

1. PyBroP2. 52, 953. 237.1 10.29

1. PyBroP2. 31, 953. 259.1 10.30

1. PyBroP2. 54, 953. 250.9 10.31

1. PyBroP2. 64, 953. 210.9 10.32

1. PyBroP2. 47, 953. 197 10.33

1. PyBroP2. 47, 953. 273 10.34

1. PyBroP2. 51, 953. 237.1 10.35

1. PyBroP2. 60, 903. 224 10.36

1. PyBroP2. 65, 993. 252 10.37

1. PyBroP2. 58, 993. 239 10.38

1. PyBroP2. 35, 993. 221.1 10.39

1. PyBroP2. 42, 993. 235.2 10.40

1. DCC2. 32, 993. 293.1 10.41

1. PyBroP2. 45, 993. 223.1 10.42

1. PyBroP2. 55, 813. 251.1 10.43

1. PyBroP2. 68, 663. 224.9 10.44

1. PyBroP2. 68, 663. 241.1 10.45

1. PyBroP2. 44, 403. 295 10.46

1. DCC2. 37, 813. 265 10.47

1. PyBroP2. 71, 953. 293.1 10.48

1. PyBroP2. 35, 993. 220.9 10.49

1. DCC2. 16, 993. 209.0 10.50

1. DCC2. 18, 993. 264.0

Preparative Example 10.55 Alternative Procedure for Preparative Example3

To the nitrosalicylic acid (3 g) dissolved dichloromethane (150 mL) atroom temperature was added oxalyl chloride (4.3 mL) and DMF (0.01 eq.).After stirring for one day the mixture was concentrated in a vacuum togive a semi solid which was used directly in step B.

To the material from step A diluted in dichloromethane (50 mL) andcooled to 0° C. was added dimethyl amine in THF (2N solution, 24.6 mL)and triethylamine (4 eq.). After stirring for 24 hours at roomtemperature the mixture was concentrated in vacuo, diluted with 1Msodium hydroxide (30 mL) and after a half hour was washed withdichloromethane. The aqueous phase was acidified with 6M HCl (aq),extracted with dichloromethane and the organic phase was washed withwater, dried over Na₂SO₄ and concentrated to give the title compound(3.2 g, 93%).

A mixture of the product from step B above (6 g), 10% Pd/C (0.6 g), andEtOH (80 mL) was stirred in a parr shaker under hydrogen (40 psi) atroom temperature for 2 days. Filtration through celite and concentrationin vacuo afforded the title product (5.1 g, 99%, MH⁺=181).

Preparative Example 11

Step A

Following a similar procedure as in Preparative Example 1 except usingdimethylamine (2M in THF, 33 mL) and 5-methylsalicylic acid (5 g), thedesired product was prepared (6.5 g).

Step B

Nitric acid (0.8 mL) in H₂SO₄ was added to a cooled (−20° C.) suspensionof the product from Step A above (3 g) in H₂SO₄ (25 mL). The mixture wastreated with 50% NaOH (aq) dropwise, extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give the productas a crude solid (2.1 g, 44%, MH⁺=225).

Step C

The product was prepared in the same manner as described in Step B ofPreparative Example 2 (0.7 g, 99%, MH⁺=195).

Preparative Example 11.1

Step A

The above amine was reacted with the acid using the procedure set forthin Preparative Example 2, Step A to yield the desired amide (54%).

Step B

Na₂S₂O₄ (1.22 g) was dissolved in water (4 ml) followed by the additionof NH₃/H₂O (300 ul). The solution ws then added to the product from StepA (200 mg) in dioxane (4 ml) and stirred for 30 min. The crude materialwas purified via flash column chromatography (CH₂Cl₂/MeOH, 20:1) to give100 mg of product (56%, MH+=251).

Preparative Example 11.2

Following the procedures set forth in Preparative Example 11.1, Steps Aand B, but using N-methylmethoxylamine, the title compound was obtained(86%, MH+=181).

Preparative Example 11.10

Step A

Following the procedure set forth in Preparative Example 1, but usingN-hydroxysuccinimide and 2% DMF in CH₂Cl₂, the desired amide wasobtained (33%, MH+=297).

Step B

Following the procedure set forth in Preparative Example 2, Step B, theamine was prepared (99%, MH+=267).

Preparative Example 11.11–11.18

Following the procedures set forth in Preparative Examples 11.11 butusing the carboxylic acid, amine, and coupling agent DCC indicated, theindicated amide products were obtained and used without furtherpurification.

Prep Carboxylic 1. % Yield Ex. acid Amine Product 2. MH⁺ 11.11

1. 45, 922. 310.0 11.12

1. 45, 952. 247.2 11.13

1. 85, 852. 251.1 11.14

1. 99, 922. 211.1 11.15

1. 48, 842. 265 11.16

1. 78, 912. 238.1 11.17

1. 67, 902. 265.1 11.18

1. 28, 992. 2.267

Preparative Example 12

Step A

Following a similar procedure as described in Preparative Example 2 StepA except using dimethylamine in place of R-(+)-3-pyrrolidinol, thedesired product was prepared.

Step B

The product from step A above (8 g) was combined with iodine (9.7 g),silver sulfate (11.9 g), EtOH (200 mL) and water (20 mL) and stirredovernight. Filtration, concentration of the filtrate, re-dissolution inCH₂Cl₂ and washing with 1M HCl (aq) gave an organic solution which wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo to affordthe product (7.3 g, 57%, MH⁺=337).

Step C

The product from Step B above (3.1 g) was combined with DMF(50 mL) andMeI (0.6 mL). NaH (60% in mineral oil, 0.4 g) was added portionwise andthe mixture was stirred overnight. Concentration in vacuo afforded aresidue which was diluted with CH₂Cl₂, washed with 1M NaOH (aq), driedover anhydrous MgSO₄, filtered and concentrated in vacuo. Purificationthrough a silica gel column (EtOAc/Hex, 1:1) gave the desired compound(1.3 g, 41%, MH⁺=351).

Step D

The product from Step D above (200 mg), Zn(CN)₂ (132 mg), Pd(PPh₃)₄ (130mg) and DMF (5 mL) were heated at 80° C. for 48 hrs, then cooled to roomtemperature and diluted with EtOAc and 2M NH₄OH. After shaking well, theorganic extract was dried over anhydrous MgSO₄, filtered, concentratedin vacuo and purified by preparative plate chromatography (Silica,EtOAc/Hex, 1:1) to give the desired compound (62 mg, 44%, MH⁺=250).

Step E

BBr₃ (1.3 mL, 1M in CH₂Cl₂) was added to a CH₂Cl₂ solution (5 mL) of theproduct from step D above (160 mg) and stirred for 30 min. The mixturewas diluted with water, extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered, and concentrated in vacuo to give the desired compound(158 mg, MH⁺=236).

Step F

A mixture of the product from step E above (160 mg), platinum oxide(83%, 19 mg), and EtOH (20 mL) was stirred under hydrogen (25–40 psi)for 1.5 hr. Filtration through celite and concentration in vacuoafforded the product (165 mg, MH⁺=206).

Preparative Example 12.1

Step A

Following a similar procedure as in Preparative Example 2, Step A exceptusing 3-(methylaminomethyl)pyridine and 3-nitrosalicylic acid, thedesired compound was prepared (41%).

Step B

The compound from Step A above (0.3 g) was diluted with chloroform (15mL) and stirred with mCPBA (0.4 g) for 2 hr. Purification by columnchromatography (silica, 10% MeOH/CH₂Cl₂) gave the pyridyl N-oxide (0.32g, 100%, MH⁺=303.9).

Step C

Following a similar procedure as in Preparative Example 11.1, Step B,but using the product from Step B above, the desired compound wasobtained (15%, MH+=274).

Preparative Example 12.2

Step A

3-Nitrosalicylic acid (4 g) in MeOH (100 mL) and concentrated H₂SO₄ (1mL) were stirred at reflux overnight, concentrated in vacuo, dilutedwith CH₂Cl₂, and dried over Na₂SO₄. Purification by columnchromatography (silica, 5% MeOH/CH₂Cl₂) gave the methyl ester (2.8 g,65%).

Step B

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step A above, the desired compound was obtained(95%, MH+=167.9).

Preparative Example 12.3

To morpholine-2-carboxilic acid (200 mg) in EtOH (40 mL) at 0° C. wasadded acetyl chloride (3 mL) and the mixture was stirred at refluxovernight. Concentration in vacuo, dilution with CH₂Cl₂ and washing withNaHCO₃ (aq) gave the title compound (99%, MH⁺=160.1).

Preparative Example 12.4

To N-Boc morpholine-2-carboxylic acid (2 g) in THF (5 ml) at 0° C. wasadded a solution of borane. THF complex (1N, 10.38 ml) and the mixturewas stirred for 30 min at 0° C., and for 2 hr at room temperature. Water(200 ml) was added to the reaction and the mixture extracted withCH₂Cl₂, dried with Na₂SO₄, and concentrated in vacuo to give 490 mg ofproduct (26%). The product was then stirred in 4N HCl/dioxane to givethe amine salt.

Preparative Example 13

Step A

Following a similar procedure as in Preparative Example 1 except usingdimethylamine (2M in THF, 50 mL) and 4-methylsalicylic acid (15 g), thedesired compound was prepared (6.3 g, 35%).

Step B

The product from step A above (1.5 g) was combined with iodine (2.1 g),NaHCO₃ (1.1 g), EtOH (40 mL) and water (10 mL) and stirred overnight.Filtration, concentration of the filtrate, re-dissolution in CH₂Cl₂ andwashing with 1M HCl (aq) gave an organic solution which was dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification byflash column chromatography (silica gel, 0.5–0.7% MeOH/CH₂Cl₂) gave theproduct (0.5 g, 20%, MH⁺=306).

Step C

Nitric acid (3.8 mL) in AcOH (10 mL) was added to the product from StepB above (0.8 g) and the mixture was stirred for 40 min. The mixture wasdiluted with water and extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to give the product as anorange solid (0.8 g, 92%, MH⁺=351).

Step D

A mixture of the product from step C above (800 mg), 10% Pd/C (100 mg),and EtOH/MeOH (40 mL) was stirred in a parr shaker under hydrogen (45psi) for 1.5 hr. Filtration through celite and concentration in vacuoafforded the title product after purification by preparative platechromatography (Silica, 10% MeOH/CH₂Cl₂, saturated with NH₄OH) to givethe product (92 mg, 22%, MH⁺=195).

Preparative Example 13.1

Step A

Following a similar procedure as in Preparative Example 2, Step A exceptusing dimethylamine (2M in THF, 23 ml) and 5-bromosalicylic acid (5 g),the desired compound was prepared (4.2 g, 75%, MH+=244).

Step B

Nitric acid (10 ml) in AcOH (100 ml) was added to the product from StepA above (2 g) and the mixture was stirred for 20 min. The mixture wasdiluted with water and extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to give the product as ayellow solid (1.9 g, 80%, MH+=289).

Step C

The product from Step B above (1.9 g) was partially dissolved in EtOH(50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl₂.2H₂O (5.74g) was added and stirred at room temperature overnight. The crudereaction was concentrated in vacuo, diluted with CH₂Cl₂ and washed withNaHCO₃, dried over anhydrous MgSO₄, filtered and concentrated in vacuoto give the product as a solid (185 mg, 9%, MH+=259).

Preparative Example 13.2

Step A

Following a similar procedure as in Preparative Example 2, Step A,except using dimethylamine (2M in THF, 29 ml) and 5-chlorosalicylic acid(5 g), the desired compound was prepared (4.5 g, 78%, MH+=200).

Step B

Nitric acid (10 ml) in AcOH (100 ml) was added to the product from StepA above (2 g) and the mixture was stirred for 20 min. The mixture wasdiluted with water and extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to give the product as a solid(2.2 g, 88%, MH+=245).

Step C

The product from Step B above (2.2 g) was partially dissolved in EtOH(50 ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl₂.2H₂O (7.01g) was added and stirred at room temperature overnight. The crudereaction was concentrated in vacuo, diluted with CH₂Cl₂ and neutralizedwith NaOH. The entire emulsion was filtered though celite, the layerswere separated and the organic layer was dried over anhydrous MgSO₄,filtered and concentrated in vacuo to give a solid (540 mg, 22%,MH+=215).

Preparative Example 13.3

Step A

3-Nitrosalicylic acid (10 g), PyBroP (20.52 g), and DIEA (28 ml) inanhydrous CH₂Cl₂ (200 ml) were combined and stirred at room temperaturefor 10 min. Dimethylamine (2M in THF, 55 ml) was added and let thereaction stir over the weekend. The mixture was extracted with 1N NaOH(aq) and the organic phase was discarded. The aqueous phase wasacidified with 1N HCl (aq), extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The oil was taken up in etherand a solid crashed out, triterated in ether to give 4.45 g of a solid(39%, MH+=211).

Step B

The product from Step A (2.99 g), K₂CO₃ (9.82 g), and iodomethane (8.84ml) were combined in acetone and heated to reflux overnight. Thereaction was filtered and concentrated in vacuo. The oil was taken up inCH₂Cl₂ and washed with 1N NaOH, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give 3.3 g of an oil (99%, MH+=225).

Step C

The crude product from Step B (3.3 g) was stirred with 10% Pd/C (350 mg)in EtOH (50 ml) under a hydrogen gas atmosphere at 20 psi overnight. Thereaction mixture was filtered through celite and the filtrate wasconcentrated in vacuo to give 2.34 g of a solid (85%, MH+=195).

Step D

The product from Step C (469 mg) was dissolved in AcOH (6 ml). 1.95M Br₂in AcOH (1.23 ml) was added dropwise to the reaction and the mixture wasstirred at room temperature for 1 hour. 50% NaOH was added to thereaction at 0° C. and the mixture was extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The crude mixturewas purified by preparative plate chromatography (Silica, 5%MeOH/CH₂Cl₂) to give the desired product (298 mg, 23%, MH+=273).

Step E

BBr₃ (2.14 ml, 1M in CH₂Cl₂) was added to a CH₂Cl₂ solution (8 ml) ofthe product from Step D above (290 mg) and stirred overnight. A solidformed and was filtered, taken up in MeOH/CH₂Cl₂ and purified bypreparative plate chromatography (Silica, 5% MeOH/CH₂Cl₂) to give thedesired product (137 mg, 49%, MH+=259).

Preparative Example 13.4

Step A

To the product from Preparative Example 13.3 Step D (200 mg) was addedphenylboronic acid (98 mg), PdCl₂(PPh₃)₂ (51 mg), and Na₂CO₃ (155 mg) inTHF/H₂O (4 ml/1 ml). The solution was heated at 80° C. overnight. EtOAcwas added to reaction and washed with 1N NaOH. The organic layer wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude mixture was purified by preparative plate chromatography (5%MeOH/CH₂Cl₂) to give 128 mg of an oil (65%, MH+=271).

Step B

Following a similar procedure as in Preparative Example 13.3 Step E andusing the product from Step A above, the desired compound was prepared(0.1 g, 69%, MH+=257.1).

Preparative Example 13.5–13.7

Following the procedures set forth in Preparative Example 13.4 but usingthe boronic acid from the Preparative Example indicated in the Tablebelow, the amine products were obtained.

1. Yield (%) Prep Ex. Boronic Acid Product 2. MH⁺ 13.5

1. 15%2. 258 13.6

1. 32%2. 325 13.7

1. 18%2. 325

Preparative Example 13.8

Step A

2-Cyanophenol (500 mg), sodium azide (819 mg), and triethylaminehydrochloride (1.73 g) were combined in anhydrous toluene and heated to99° C. overnight. After the reaction cooled down, product was extractedwith H₂O. Aqueous layer was acidified with conc. HCl dropwise giving aprecipitate, which was filtered to give the product (597 mg, 87%,MH+=163).

Step B

Nitric acid (0.034 ml) in AcOH (5 ml) was added to the product from StepA above (100 mg) in AcOH and the mixture was allowed to stir for 1 hr.CH₂Cl₂ and H₂O were added to reaction. The organic layer was dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give an oil.Trituration in ether gave the product as a solid (12 mg, 9%, MH+=208).

Step C

The product from step C (56 mg) was stirred with 10% Pd/C (20 mg) inEtOH/MeOH (15 ml) under a hydrogen gas atmosphere overnight. Thereaction mixture was filtered through celite, the filtrate wasconcentrated in vacuo to give 29 mg is of a solid (62%, MH+=178).

Preparative Example 13.9

The amine was prepared following the procedure disclosed in WO PatentApplication 01/68570.

Preparative Example 13.10

The amine was prepared following the procedure disclosed in WO PatentApplication 01/68570.

Preparative Example 13.11

Step A

Following the procedure described in Preparative Example 88.2, Step A,the ketone was prepared (6.4 g, 36%).

Step B

To a solution of ketone (1 g) and 2-R-methylbenzylamine (0.73 ml) inanhydrous toluene (20 ml) was added 1N TiCl₄ in toluene (3 ml) at roomtemperature for 1.5 hrs. The precipitate was filtered and the filtratewas concentrated in vacuo and purified via flash column chromatography(Hex/EtOAc, 18/1) to give 800 mg of product (71%).

Step C

The imine from above (760 mg) and DBU (800 ul) were stirred withoutsolvent for 4 hr. The crude reaction was concentrated in vacuo andpurified via flash column chromatography (Hex/EtOAc, 8/1) to give 600 mgof product (79%).

Step D

The imine from Step C (560 mg) was dissolved in ether (8 ml). 3N HCl (5ml) added and let stir at room temperature overnight. The ether layerwas separated and concentrated in vacuo to give 400 mg of the aminehydrochloride product (93%).

Preparative Example 13.12

The title compound was prepared similarly as in Preparative Example13.11, but using the 2-S-methylbenzylamine instead of2-R-methylbenzylamine (69%).

Preparative Example 13.13

Step A

At room temperature, CsF (60 mg) was added to a mixture offurfuraldehyde (1.3 ml) and TMS-CF₃ (2.5 g) and stirred at roomtemperature (24 h) and refluxed for another 12 h. 3N HCl (40 ml) wasadded and after 4 hr, the mixture was extracted with ether, washed withbrine, dried over MgSO₄, and concentrated in vacuo to give the product(2.6 g, 100%).

Step B

To a solution of alcohol from above (2.6 g) in CH₂Cl₂ at roomtemperature was added Dess-Martin reagent (10 g) portionwise and 1 dropof water. After stirring for 3 hr at room temperature, 10% Na₂S₂O₃ (60ml) was added and after stirring overnight, the solid was filtered offand the filtrate was extracted with CH₂Cl₂. The organic layer was washedwith saturated sodium bicarbonate, dried with MgSO₄, filtered andconcentrated in vacuo. Ether/hexane (1:2; 30 ml) was added to theresidue, filtered, and filtrate concentrated in vacuo to give theproduct (2 g, 78%).

Step C

Following the procedures described in Preparative Example 13.11, StepsB, C and D, the amine salt was prepared.

Preparative Examples 13.15–13.17B

Following the procedure set forth in Preparative Example 13.13, butusing the prepared or commercially available aldehydes, the opticallypure amine products in the Table below were obtained.

Prep Ex. Aldehyde Amine Product Yield (%) 13.15

20% 13.16

31% 13.17

66% 13.17A

38% 13.17B

31%

Preparative Example 13.18

The title compound was prepared from trifluorophenylketone according tothe procedures described in Preparative Example 13.11, Steps B, C, and D(68%).

Preparative Example 13.19

Step A

Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) wasdissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol)was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol).The mixture was heated to reflux and continued for 6 h. After cooled toroom temperature, the mixture was filtered, the solid material wasrinsed with acetone (˜200 mL). The filtrate and rinsing wereconcentrated under reduced pressure to a solid, further dried on highvacuum, yielding 13.7 g (100%) ofmethyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH⁺=251.0).

Step B

Methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (13.7 g), available fromstep A, was dissolved in 75 mL of THF, and added with a 1.0 M sodiumhydroxide aqueous solution (65 mL, 65.0 mmol). The mixture was stirredat room temperature for 24 h. A 1.0 M hydrogen chloride aqueous solutionwas added dropwise to the mixture until pH was approximately 2. Theacidic mixture was extracted with CH₂Cl₂ (100 mL×2, 50 mL). The combinedorganic extracts were washed with brine (40 mL), dried with Na₂SO₄, andconcentrated under reduced pressure to a solid, 10.0 g (100%, over twosteps) of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (MH⁺=237.0).

Step C

To a stirred solution of 3-methoxy-4-bromo-2-thiophenecarboxylic acid(6.5 g, 27.4 mmol) in 140 mL of CH₂Cl₂, obtained from step B, was addedbromo-tripyrrolidinophosphonium hexafluorophosphate (PyBrop, 12.8 g,27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, themixture was diluted with 100 mL of CH₂Cl₂, and washed with a 1.0 Msodium hydroxide aqueous solution (30 mL×3) and brine (30 mL). Theorganic solution was dried with Na₂SO₄, filtered, and concentrated to anoil. This crude oil product was purified by flash column chromatography,eluting with CH₂Cl₂-hexanes (1:1, v/v). Removal of solvents afforded asolid, further dried on high vacuum, yielding 6.76 g (93%) ofN,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH⁺=265.0,M+2=266.1).

Step D

An oven dried three-neck round bottom flask was equipped with arefluxing condenser, charged sequentially with palladium acetate (95 mg,0.42 mmol), (R)-BINAP (353 mg, 0.57 mmol), cesium carbonate (9.2 g,28.33 mmol), and N,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide(3.74 g, 14.2 mmol, from step C). The solid mixture was flushed withnitrogen. Toluene (95 mL) was added to the solid mixture followed bybenzophenone imine (3.6 mL, 21.5 mmol). The mixture was heated to refluxand continued for 10 h. A second batch of palladium acetate (95 mg, 0.42mmol) and (R)-BINAP (353 mg, 0.57 mmol) in 5 mL of toluene was added.Refluxing was continued for 14 h. The third batch of palladium acetate(30 mg, 0.13 mmol) and (R)-BINAP (88 mg, 0.14 mmol) was added, andreaction continued at 110° C. for 24 h. The mixture was cooled to roomtemperature, diluted with ether (50 mL), filtered through a layer ofCelite, rinsing with ether. The filtrate and rinsing were concentratedunder reduced pressure to an oil, which was purified twice by flashcolumn chromatography using CH₂Cl₂ and CH₂Cl₂-MeOH (200:1) as eluents.Removal of solvents afforded 4.1 g (79%) of the amido-thiophenediphenylimine product as a solid (MH⁺=365.1).

Step E

To a stirred solution of thiophene imine (5.09 g, 13.97 mmol), obtainedfrom step D, in 140 mL of CH₂Cl₂ at −78° C. was added dropwise a 1.0 Msolution of boron tribromide in CH₂Cl₂. The mixture was stirred for 3 hwhile the temperature of the cooling bath was increased slowly from −78°C. to −15° C. 100 mL of H₂O was added, the mixture was stirred at roomtemperature for 30 min, then the two layers were separated. The organiclayer (as A) was extracted with H₂O (30 mL×2). The aqueous layer andaqueous extracts were combined, washed with CH₂Cl₂ (30 mL), and adjustedto pH ˜8 using a saturated NaHCO₃ aqueous solution. The neutralizedaqueous solution was extracted with CH₂Cl₂ (100 mL×3), the extracts werewashed with brine, dried with Na₂SO₄, and concentrated under reducedpressure to a light yellow solid, 1.49 g ofN,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide (first crop). Theprevious separated organic layer A and organic washing were combined,stirred with 30 mL of a 1.0 M HCl aqueous solution for 1 h. The twolayers were separated, the aqueous layer was washed with CH₂Cl₂ (30 mL)and adjusted to pH˜8 using a saturated NaHCO₃ aqueous solution, and theseparated organic layer and organic washing were combined as organiclayer B. The neutralized aqueous solution was extracted with CH₂Cl₂ (30mL×4), the extracts were washed with brine, dried by Na₂SO₄, andconcentrated under reduced pressure to give 0.48 g of a solid as thesecond crop of the titled product. Organic layer B from above was washedwith brine, and concentrated to an oil, which was separated bypreparative TLC (CH₂Cl₂-MeOH=50:1) to afford 0.45 g of a solid as thethird crop of the titled product. The overall yield of the product,N,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide, is 2.32 g (89%)(MH⁺=187.0).

Preparative Example 13.20

Step A

To the product from Preparative Example 13.19 Step D (1.56 g) in CH₂Cl₂(55 ml) was added potassium carbonate (1.8 g) followed by dropwiseaddition of bromine (0.45 ml). After 5 hr of mixing, water (100 ml) wasadded to the reaction and the layers were separated. The aqueous layerwas extracted with CH₂Cl₂, which was then washed with brine, saturatedsodium bicarbonate, and brine again. The organic layer was dried withNa₂SO₄, and concentrated in vacuo. The residue was purified via flashcolumn chromatography (CH₂Cl₂) to yield 1.6 g of product (83%).

Step B

The product from above was reacted in the procedure set forth inPreparative Example 13.19 Step C to give the amine.

Preparative Example 13.21

Step A

To the product from Preparative Example 13.20, Step A (300 mg) in THF (7ml) at −78° C. was added a solution of n-BuLi (1.6M in hexanes, 0.54ml). After 1 hr, iodomethane (0.42 ml) was added dropwise. After 3 hrsof stirring at −78° C., the reaction was warmed to room temperatureovernight. Saturated ammonium chloride and water were added to thereaction and extracted with CH₂Cl₂. The organic layer was washed withsaturated sodium bicarbonate and brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by preparativeplate chromatography (CH₂Cl₂-MeOH=70:1 to 50:1) to afford the product(111 mg, 43%).

Step B

The product from above was reacted in the procedure set forth inPreparative Example 13.19, Step E to give the amine.

Preparative Example 13.22

Step A

To the product from Preparative Example 13.19 (400 mg), Step D inCH₂Cl₂-pyridine (14 ml) was added N-chlorosuccinimide (220 mg). Themixture was stirred for 5 hr and then diluted with CH₂Cl₂ and washedwith water, saturated sodium bicarbonate and brine, and concentrated invacuo. The crude product was purified via preparative platechromatography (CH₂Cl₂-MeOH=50:1) to give 180 mg of product (64%).

Step B

The product from above (274 mg) was reacted in the procedure set forthin Preparative Example 13.19, Step E to give the amine (89 mg, 58%).

Preparative Example 13.23

Step A

To a stirred solution of acid (630 mg) from Preparative Example 13.19,Step B in CH₂Cl₂ (25 ml) was added oxalyl chloride (235 ul) followed bya catalytic amount of DMF (10 ul). The mixture was stirred for 1 hr,then potassium carbonate (1.8 g) was added followed by3-amino-5-methylisoxazole (443 mg). The reaction stirred overnight andwas quenched with water (25 ml). Layers were separated and the organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was purified by preparative platechromatography (CH₂Cl₂) to afford the product (580 mg, 78%,MH+=317,319).

Step B

The acid from the above (750 mg) step was reacted following theprocedure set forth in Preparative Example 13.3, Step B to yield 625 mgof product (80%, MH+=331).

Step C

The product from above was reacted following the procedure set forth inPreparative Example 13.19, Step D to yield 365 mg of product (53%)

Step D

The product from above was reacted following the procedure set forth inPreparative Example 13.19, Step E to give the amine product (MH+=254).

Preparative Example 13.25

Step A

To a solution of 2-methylfuran (1 g) in ether (30 ml) was added n-BuLi(5.32 ml) at −78° C. The reaction was warmed to room temperature andthen refluxed at 38° C. for 1 hr. The reaction was cooled back down to−78° C. where the furyl lithium was quenched with trifluorobutyraldehydeand let stir at room temperature overnight. Saturated ammonium chlorideadded and extracted with ether. Purified via flash column chromatographyto yield pure product (2 g, 80%)

Step B

The azide was prepared using the procedure from Preparative Example75.75, Step B and the alcohol (1 g) from above and carried on crude toStep C below.

Step C

The amine was prepared using the procedure from Preparative Example75.75, Step C to yield 400 mg of an oil (53%).

Preparative Example 13.26

Step A

Perfluoroiodide (3.6 ml) was condensed at −78° C. Ether (125 ml) wasadded followed by the methyllithium.lithiumbromide complex (1.5M inether, 18.4 ml). After 15 min, a solution of 5-methylfuraldehyde (2.5ml) in ether was added dropwise. The reaction was warmed to −45° C. andlet stir for 2 hr. Saturated ammonium chloride (30 ml) and water (30 ml)were added and let stir at room temperature for 1 hr. The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂. The organiclayer was washed with brine, dried with Na₂SO₄, filtered andconcentrated in vacuo to give 5.86 g of product (100%).

Step B

The alcohol from above was reacted to form the azide using the procedureset forth in Preparative Example 75.75 Step B.

Step C

The azide from above was reacted to form the racemic amine using theprocedure set forth in Preparative Example 75.75 Step C.

Preparative Example 13.27

Step A

Following the procedure set forth in Preparative Example 13.26, Step A,the alcohol was prepared (100%).

Step B

To a solution of the alcohol (500 mg) from step A above in CH₂Cl₂ (20ml) was added N-methyl-morpholine monohydrate (575 mg) and a catalyticamount of tetrapropyl ammonium perruthenate (76 mg). After 3 hr, themixture was diluted with hexane (10 ml) and filtered through a silicapad, rinsing with hexane: CH₂Cl₂ (200 ml). The filtrate was concentratedin vacuo to give 350 mg of product (70.7%)

Step C

The ketone (1.19 g) from Step B was dissolved in THF (9.5 ml) and cooledto 0° C. A solution of S-methyl oxazoborolidine (1M in toluene, 1 ml)followed by a solution of borane complexed with dimethylsulfide (9.5 ml,2M in THF) was added to the solution. The mixture was stirred at 0° C.for 30 min and continued at room temperature for 5 hr. The mixture wascooled back down to 0° C. and methanol (15 ml) was added dropwise to themixture. After 30 min, the mixture was concentrated in vacuo to give anoily residue.

The residue was dissolved in CH₂Cl₂ and washed with 1N HCl, water, andbrine. Dried with Na₂SO₄, filtered and concentrated in vacuo. The crudematerial was purified via flash column chromatography (Hex/CH₂Cl₂, 1:1)to afford 1.14 g of an oil (67%).

Step D

The alcohol (1.14 g) from above was reacted to form the azide using theprocedure set forth in Preparative Example 75.75 Step B.

Step E

The azide (1.11 g) from above was stirred with 10% Pd/C (280 mg) in EtOH(40 ml) under a hydrogen gas atmosphere overnight. The reaction wasfiltered through celite, the filtrate was concentrated in vacuo to give700 mg of product (70%).

Preparative Example 13.28

Step A

To a stirred solution of 1-(2-thienyl)-1-propanone (3 g) in aceticanhydride (6 ml) at 0° C. was added dropwise a solution of fuming nitricacid in acetic acid (2 ml in 10 ml). After 30 min, the reaction waswarmed to room temperature and let stir for 5 hrs where a solidprecipitated out. Ice was added to the reaction and the solid wasfiltered. The solid was purified by flash column chromatography(Hex/CH₂Cl₂, 3:1 and 2:1) to yield 800 mg of desired product (20%).

Step B

The above nitro-thiophene compound (278 mg) was reduced using theprocedure set forth in Preparative Example 2, Step B to give 54 mg ofproduct (23%).

Step C

The above amine (395 mg), TEA (1 ml) and methanesulfonylchloride (0.5ml) were combined in CH₂Cl₂ (35 ml) and stirred at room temperature for1 hr. The reaction was quenched with saturated sodium bicarbonate (15ml). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to afford product (854 mg, 100%).

Step D

To the above product (854 mg) in THF (25 ml) was added dropwise asolution of tetrabutylammonium fluoride (1M in THF, 2.8 ml). The mixturewas stirred overnight, then diluted with CH₂Cl₂ (30 ml), washed withammonium chloride and brine, dried over over Na₂SO₄, filtered andconcentrated in vacuo to afford product (2.36 g, >100%).

Step E

The ketone (2.36 g) above was reacted via the procedure set forth inPreparative Example 88.2, Step B to yield 547 mg of product (86.6%).

Step F

To the product from step E (310 mg) in dimethoxyethane (12 ml) was addeddropwise a solution of LAH (1M in ether, 3.8 ml). The mixture was heatedto reflux overnight. The reaction was cooled to room temperature, SiO₂was added as well as water (1 ml) dropwise and let stir for 15 min. Themixture was filtered and the filtrate was concentratred in vacuo. Thecrude product was purified by preparative plate chromatography(MeOH/CH₂Cl₂, 15:1) to give the amine product (40 mg, 14%).

Preparative Example 13.29

Step A

To a solution of 3-methoxythiophene (3 g) in dichloromethane (175 mL) at−78° C. was added chlorosulfonic acid (8.5 mL) dropwise. The mixture wasstirred for 15 min at −78° C. and 1.5 h at room temp. Afterwards, themixture was poured carefully into crushed ice, and extracted withdichloromethane. The extracts were washed with brine, dried overmagnesium sulfate, filtered through a 1-in silica gel pad. The filtratewas concentrated in vacuo to give the desired compound (4.2 g).

Step B

The product from Step A above (4.5 g) was dissolved in dichloromethane(140 mL) and added with triethylamine (8.8 mL) followed by diethyl aminein THF (2M, 21 mL). The resulting mixture was stirred at roomtemperature overnight. The mixture was washed with brine and saturatedbicarbonate (aq) and brine again, dried over sodium sulfate, filteredthrough a 1-in silica gel pad. The filtrate was concentrated in vacuo togive the desired compound (4.4 g).

Step C

The product from Step B above (4.3 g) was dissolved in dichloromethane(125 mL) and cooled in a −78° C. bath. A solution of boron tribromide(1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirredfor 4 h while the temperature was increased slowly from −78° C. to 10°C. H₂O was added, the two layers were separated, and the aqueous layerwas extracted with dichloro-methane. The combined organic layer andextracts were washed with brine, dried over magnesium sulfate, filtered,and concentrated in vacuo to give 3.96 g of the desiredhydroxy-compound.

Step D

The product from step C above (3.96 g) was dissolved in 125 mL ofdichloromethane, and added with potassium carbonate (6.6 g) followed bybromine (2 mL). The mixture was stirred for 5 h at room temperature,quenched with 100 mL of H₂O. The aqueous mixture was adjusted to pH˜5using a 0.5N hydrogen chloride aqueous solution, and extracted withdichloromethane. The extracts were washed with a 10% Na₂S₂O₃ aqueoussolution and brine, dried over sodium sulfate, and filtered through acelite pad. The filtrate was concentrated in vacuo to afford 4.2 g ofthe desired bromo-compound.

Step E

The product from Step D (4.2 g) was dissolved in 100 mL of acetone andadded with potassium carbonate (10 g) followed by iodomethane (9 mL).The mixture was heated to reflux and continued for 3.5 h. After cooledto room temperature, the mixture was filtered through a Celite pad. Thefiltrate was concentrated in vacuo to a dark brown residue, which waspurified by flash column chromatography eluting withdichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desired product.

Step F

The product from step E (2.7 g) was converted to the desired iminecompound (3 g), following the similar procedure to that of PreparativeExample 13.19 step D.

Step G

The imine product from step F (3 g) was dissolved in 80 mL ofdichloromethane and cooled in a −78° C. bath. A solution of borontribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. Themixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane. The organic layer and extracts were combined,washed with brine, and concentrated to an oily residue. The residue wasdissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) andhydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. Themixture was poured into an aqueous mixture of sodium hydroxide (1.0 Maq, 50 mL) and ether (100 mL). The two layers were separated. Theaqueous layer was washed with ether three times. The combined etherwashings were re-extracted with H₂O once. The aqueous layers werecombined, washed once with dichloromethane, adjusted to pH ˜6 using 3.0M and 0.5 M hydrogen chloride aqueous solutions, and extracted withdichloromethane. The organic extracts were combined, washed with brine,dried over sodium sulfate, and concentrated in vacuo to give 1.2 g ofdesired amine compound.

Preparative Examples 13.30–13.32

Following the procedures set forth in Preparative Example 13.29, butusing commercially available amines, hydroxy-amino-thiophene products inthe Table below were obtained.

Yield (%) Prep Ex. Amine Product MH⁺ 13.30 Bn₂NH

10%375.1 13.31 MeBnNH

14%299.0 13.32 EtBnNH

22% 13.32A (Et)₂NH

25%

Preparative Example 13.33

Step A

2-Chlorosulfonyl-3-methoxy-thiophene (4.0 g, 18.8 mmol), the productfrom step A of Preparative Example 13.29, was converted to3-methoxy-2-ethylbenzylsulfonyl-thiophene (5.5 g, 94%, MH⁺=312.1) byusing ethylbenzyl-amine, following the procedure set forth inPreparative Example 13.29, Step B.

Step B

The product from step A above (5.5 g, 17.70 mmol) was demethylatedfollowing the procedure set forth in Preparative Example 13.29, Step C.The alcohol product was obtained in 4.55 g (87%, MH⁺=298.0).

Step C

The product from Step B above (4.55 g, 15.30 mmol) was brominated usingthe procedure set forth in Preparative Example 13.29, Step D. Thecorresponding bromide was obtained in 4.85 g (84%).

Step D

The bromo-alcohol from Step C above (4.84 g, 12.86 mmol) was methylatedusing the procedure set forth in Preparative Example 13.29, Step E. Theproduct was obtained in 4.82 g (96%).

Step E

The product from Step D above (4.82 g, 12.36 mmol) was stirred withconcentrated sulfuric acid (5 mL) at room temperature for 3 h. Ice water(30 mL) was added to the mixture followed by CH₂Cl₂ (50 mL). The aqueousmixture was adjusted to pH˜6 using a 1.0 M NaOH aqueous solution. Thelayers were separated. The aqueous layer was extracted with CH₂Cl₂ (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to a dark brown oil, which was purified byflash column chromatography, eluting with CH₂Cl₂-hexanes (1:1, v/v).Removal of solvents afforded 3.03 g (82%) of the debenzylated product(M⁺=300.0, M+2=302.0).

Step F

The product from Step E (1.34 g, 4.45 mmol) was methylated using theprocedure set forth in Preparative Example 13.29, Step E. The desiredproduct was obtained in 1.36 g (97%, M⁺=314.1, M+2=316.0).

Step G

The product from Step F (1.36 g, 4.33 mmol) was converted to imineproduct (1.06 g, 55%, MH⁺=415.1) using the procedure set forth inPreparative Example 13.29, Step F.

Step H

The imine product from Step G (1.06 g, 2.56 mmol) was converted to thedesired hydroxy-amino thiophene compound (0.26 g, 43%) using theprocedure set forth in Preparative Example 13.29, Step G.

Preparative Example 13.34

Step A

2-Chlorosulfonyl-3-methoxy-thiophene (3.8 g, 17.87 mmol), the productfrom step A of Preparative Example 13.29, was dissolved in 100 mL ofCH₂Cl₂ and 20 mL of pyridine. 3-Amino-5-methyl-isoxazole (3.5 g, 35.68mmol) was added. The mixture was stirred for 20 h at room temperature,diluted with 100 mL of CH₂Cl₂, and washed with a 0.5 N HCl aqueoussolution (50 mL×2), H₂O (50 mL), and brine (50 mL). The organic solutionwas dried with Na₂SO₄, and concentrated in vacuo to a brown oil. Thisoil was dissolved in 100 mL of CH₂Cl₂, washed again with a 0.5 M HClaqueous solution (30 mL×3) and brine. After dried over Na₂SO₄, theorganic solution was concentrated in vacuo to a yellow solid, 4.48 g(91%, MH⁺=275.0) of the desired product.

Step B

The product from Step A above (4.48 g, 16.33 mmol) was dissolved inacetone (100 mL), added with potassium carbonate (5.63 g, 40.80 mmol)and iodomethane (10.1 mL, 163.84 mmol). The mixture was stirred at roomtemperature for 1.5 h, diluted with 100 mL of hexanes and 50 mL ofCH2Cl2, and filtered through a 1-in silica gel pad, rinsing with CH₂Cl₂.The filtrate was concentrated under reduced pressure to give 4.23 g(90%, MH⁺=289.0) of the desired product as a light yellow solid.

Step C

To a stirred suspension of sodium hydride (130 mg, 95%, 5.4 mmol) in 8mL of N,N′-dimethylforamide at room temperature was added ethanethiol(0.45 mL, 6.0 mmol) dropwise. After 5 min, the mixture became a clearsolution, and was added to a stirred solution of the product obtainedfrom Step B above (0.45 g, 1.56 mmol) in 2 mL of N,N′-dimethylforamidein a round bottom flask. The flask was sealed with a ground glassstopper, and the mixture was heated at 90–95° C. for 4 h. After cooledto room temperature, the mixture was poured into 20 mL of a 1.0 M NaOHaqueous solution, further rinsed with 20 mL of H₂O. The aqueous mixturewas washed with diethyl ether (30 mL×2), adjusted to PH ˜5 using a 0.5 MHCl aqueous solution, and extracted with CH₂Cl₂ (50 mL×4). The combinedextracts were washed with brine, dried (Na₂SO₄), and concentrated to adark yellow solution. This was dissolved in 50 mL of ethyl acetate,washed with H₂O (30 mL×2) and brine (30 mL), dried over Na₂SO₄.Evaporation of solvent gave 0.422 g of the alcohol product (99%,MH⁺=275.0).

Step D

The alcohol obtained from Step C above (0.467 g, 1.70 mmol) wasbrominated using the procedure set forth in Preparative Example 13.29,Step D, to afford the corresponding bromide in 0.607 g (100%).

Step E

The bromide obtained from Step D above (0.607 g, 1.72 mmol) wasmethylated using the procedure set forth in Preparative Example 13.29,Step E, to give the desired product in 0.408 g (65%, M⁺=367, M+2=369.1).

Step F

The product (0.405 g, 1.103 mmol) from Step E above was converted to theimine compound (0.29 g, 56%) using the procedure set forth inPreparative Example 13.29, Step F.

Step G

The imine product obtained from Step F above (0.29 g, 0.61 mmol) wasdemethylated using the procedure set forth in Step C above to give thecorresponding alcohol as a dark yellow oil, which was dissolved in 5 mLmethanol and added with sodium acetate (0.12 g, 1.46 mmol) andhydroxyamine hydrochloride (0.075 g, 1.08 mmol). The resulting mixturewas stirred at room temperature for 3 h, and poured into 10 mL of 1.0 MNaOH aqueous solution. 30 mL of H₂O was used as rinsing and combined tothe aqueous layer. The aqueous mixture was washed with diethyl ether (40mL×3), adjusted to pH˜6 using a 1.0 M HCl aqueous solution, andextracted with ethyl acetate (40 mL×3). The organic extracts were washedwith H₂O (20 mL×2), brine (20 mL), dried over Na₂SO₄, and concentratedin vacuo to give 0.112 g of the desired hydroxy-amino thiophenesulfonamide (64%, MH⁺=290).

Preparative Example 13.35

Step A

To a solution of 2-methyl furan (1.72 g) in ether was added BuLi (8.38mL) at −78° C. and stirred at room temperature for half an hour. Thereaction mixture again cooled to −78° C. and quenched with cyclopropylamide 1 and stirred for two hours at −78° C. and slowly warmed to roomtemperature. The reaction mixture stirred for three hours at roomtemperature and quenched with the addition of saturated ammoniumchloride solution. The mixture was taken to a separatory funnel, washedwith water, brine and dried over anhydrous sodium sulfate. Filtrationand removal of solvent afforded the crude ketone, which was purified byusing column chromatography to afford the ketone 3.0 g (87%) as a paleyellow oil.

Step B

To a solution of ketone (1.0 g) in THF (5.0 mL) at 0° C. was addedR-methyl oxazoborolidine (1.2 Ml, 1M in toluene) dropwise followed byaddition of a solution of borane complexed with dimethyl sulfide (1.85mL, 2M in THF). The reaction mixture was stirred for 30 minutes at 0° C.and than at room temperature for one hour. The reaction mixture wascooled to 0° C. and MeOH was added carefully. The mixture was stirredfor 20 minutes and was concentrated under reduced pressure. The residuewas extracted with ether, washed with water, 1M HCl (10 mL), saturatedsodium bicarbonate (10.0 mL) water and brine. The organic layer wasdried over anhydrous sodium sulfate, filtered and removal of solventafforded the crude alcohol which was purified by silica gelchromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

Preparative Example 13.36

Step A

An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) wasmixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours. Aftercooling the reaction mixture, water (10 mL) was added, followed bysaturated sodium carbonate solution until it becomes alkaline. Thereaction mixture was extracted with ether several times and the combinedether layer was washed with water, brine and dried over anhydrous sodiumsulfate. Filtration and removal of solvent afforded the crude ketone,which was purified by using silica gel chromatography to afford theketone 0.9 g (43%) as a yellow oil.

Step B

The step B alcohol was obtained following a similar procedure set forthin the preparative example 13.35 Step B.

Preparative Example 13.37

Step A:

To a solution of 5-methyl furan-2-aldehyde (1.0 g) and3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indiumpowder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture wasstirred over night, diluted with water and extracted with ether. Theether layer was washed with water, brine and purified by silicagelchromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 13.38–13.45

Following a similar procedure set forth in Preparative Examples 13.25and 13.35, and using the indicated Furan and Electrophile, the followingAlcohols in the Table below were prepared.

Prep. ex Furan Electrophile Alcohol Yield 13.38

86% 13.39

69% 13.40

84% 13.41

82% 13.42

60% 13.43

65% 13.44

82% 13.45

89%

Preparative Examples 13.50–13.61

Following a similar procedure set forth in Preparative Examples 13.25,and using the indicated Alcohol, the following Amines in the Table belowwere prepared.

PREP. EX. ALCOHOL AMINE % YIELD 13.50 13.45

28% 13.51 13.38

58% 13.52 13.36

69% 13.53 13.35

81% 13.54 13.37

82% 13.55 13.39

45% 13.56 13.41

57% 13.57 13.40

58% 13.58 13.44

54% 13.59 13.42

53% 13.60 13.43

50% 13.61 13.37

82%

Preparative Example 13.70

Step A

The imine was prepared following the procedure set forth in thepreparative example 13.19 from the known bromoester (1.0 g) as a yellowsolid, Step A to yield 1.1 g (79%).

Step B

The Step A product (0.6 g) was reacted following the procedure set forthin the preparative example 13.19 to give the amine product 0.19 g (64%).

Step C

The Step B product (1.0 g) was reacted following the procedure set forthin the preparative example 13.19 to give the acid as yellow solid 0.9 g(94%)

Step D

The Step C product (0.35 g) was reacted following the procedure setforth in the preparative example 13.19 to give the amino acid as yellowsolid 0.167 g (93%).

Preparative Example 14

Step A

3-Nitro-1,2-phenylenediamine (10 g), sodium nitrite (5.4 g) and aceticacid (20 mL) were heated at 60° C. overnight, then concentrated invacuo, diluted with water and extracted with EtOAc. The productprecipitated from the organic phase (5.7 g) as a solid and used directlyin step B.

Step B

The product from Step A above (2.8 g) was stirred with 10% Pd/C (0.3 g)in MeOH (75 mL) under a hydrogen gas atmosphere overnight. The reactionmixture was filtered through celite and the filtrate concentrated invacuo, to give the product (2.2 g, MH+=135).

Preparative Example 15

Step A

N-methyl-4-bromopyrazole-3-carboxylic acid was prepared according toknown methods, see: Yu. A. M.; Andreeva, M. A.; Perevalov, V. P.;Stepanov, V. I.; Dubrovskaya, V. A.; and Seraya, V. I. in Zh. Obs. Khim.(Journal of General Chemistry of the USSR) 1982, 52, 2592, and refscited therein.

Step B

To a solution of N-methyl-4-bromopyrazole-3-carboxylic acid (2.0 g),available from step A, in 65 mL of anhydrous DMF was addedbromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 4.60 g),dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL)at 25° C. The mixture was stirred for 26 h, and concentrated underreduced pressure to an oily residue. This residue was treated with a 1.0M NaOH aqueous solution, and extracted with ethyl acetate (50 mL×4). Theorganic extracts were combined, washed with brine, and dried withanhydrous Na₂SO₄. Removal of solvents yielded an oil, which was purifiedby preparative thin layer chromatography, eluting with CH₂Cl₂-MeOH(20:1), to give 1.09 g of the amide product (48%, MH⁺=232.0).

Step C

To a solution of the amide (0.67 g), obtained from step B, in 8 mL ofconcentrated sulfuric acid at 0° C. was added potassium nitrate (1.16 g)in small portions. The cooling bath was removed and the mixture washeated at 110° C. for 6 h. After cooling to 25° C., the mixture waspoured into 80 mL of H₂O, and an additional 20 mL of H₂O was used as arinse. The aqueous mixture was extracted with CH₂Cl₂ (100 mL×4). Thecombined extracts were washed with brine (50 mL), sat. NaHCO₃ aqueoussolution (50 mL), brine (50 mL), and dried with Na₂SO₄. Evaporation ofsolvent gave an oil, which solidified on standing. The crude product waspurified by flash column chromatography, eluting with CH₂Cl₂-MeOH (1:0,50:1 and 40:1). Removal of solvents afforded 0.521 g (65%) of theproduct as a solid (MH⁺=277.1)

Step D

The product (61 mg) obtained from step C was dissolved in 3 mL of THF.To this solution at −78° C. was added dropwise along the inside wall ofthe flask a 1.6 M solution of n-butyl lithium in hexane. After 45 min, asolution of methyl borate (0.1 mL) in THF (1.0 mL) was added. After 1.5h, a solution of acetic acid in THF (0.25 mL, 1:10 v/v) was added to thecold mixture. Stirring was continued for 10 min, and a 30 wt % aqueoushydrogen peroxide solution (0.1 mL) was added. An additional portion ofhydrogen peroxide aqueous solution (0.05 mL) was added 20 min later. Thecooling bath was removed, and the mixture was stirred at 25° C. for 36h. The mixture was poured into 30 mL of H₂O, and the aqueous mixture wasextracted with ethyl acetate (30 mL×4). The extracts were combined,washed with brine (10 mL), 5% NaHCO₃ aqueous solution (10 mL) and brine(10 mL). The organic layer was dried with Na₂SO₄ and concentrated underreduced pressure to a residue, which was then purified by preparativethin layer chromatography eluting with CH₂Cl₂-MeOH (20:1) to give thehydroxylated product (5 mg, 10%, MH⁺=215.3).

Step E

By treating the hydroxylated product of Step E with H₂ under theconditions of 10% palladium on carbon in ethanol, one would obtain thedesired hydroxyl-amino compound.

Preparative Example 16

Step A

Following a similar procedure used in Preparative Example 13, Step Cexcept using the known compound, 4-methyl-pyrimidin-5-ol, the productcan be prepared.

Step B

Following a similar oxidation procedure used in Preparative Example 15,Step A except using the compound from Step A above, the product can beprepared.

Step C

Following a similar procedure used in Preparative Example 11, Step Aexcept using the compound from Step B above, the product can beprepared.

Step D

Following a similar procedure used in Preparative Example 12, Step Fexcept using the compound from Step C above, the product can beprepared.

Preparative Example 17

Step A

Following a similar procedure used in Preparative Example 11, Step Aexcept using the known 4-hydroxynicotinic acid, the product can beprepared.

Step B

Following a similar procedure used in Preparative Example 13, Step Cexcept using the compound from Step A above, the product can beprepared.

Step C

Following a similar procedure used in Preparative Example 12, Step Fexcept using the compound from Step C above, the product can beprepared.

Preparative Example 18

Step A

Following a similar procedure used in Preparative Example 13, Step Cexcept using the compound from Step A above, the product can beprepared.

Step B

Stirring the compound from Step A above, a suitable Pt or Pd catalystand EtOH under hydrogen atmosphere (1–4 atm) the product can beprepared.

Preparative Example 19

The product from Preparative Example 3 (14.6 g) dissolved in absoluteEtOH (100 mL) was added dropwise over 4 hours to a stirred ethanolic(100 mL) solution of diethylsquarate (19 mL, 128 mmol). After 5 days,the reaction mixture was concentrated in vacuo, and the resultingresidue purified by column chromatography (silica gel, 0–5% MeOH/CH₂Cl₂)gave the product (65%, MH⁺=305, mp=178.6° C.).

Preparative Example 19.1

The amine from Prepartive Example 3 (5 g) and dimethylsquarate (3.95 g)in MeOH were stirred overnight. The precipitated product was filtered togive 6.32 g of solid (78%, MH+=291.1)

Preparative Example 19.2

The hydroxy thiophene amine from Preparative Example 13.34 (108 mg, 0.37mmol) was dissolved in 5 mL of ethanol and stirred with diethoxysquarate(0.14 mL, 0.95 mmoL) and potassium carbonate (52 mg, 0.38 mmol) at roomtemperature overnight. The mixture was diluted with H2O (25 mL),adjusted to pH˜6 using a 1.0 M HCl aqueous solution, and extracted withethyl acetate (40 mL×3). The combined organic extracts were washed withbrine, dried over Na2SO4, and concentrated to an oil, which was purifiedby flash column chromatography, eluting with CH2Cl2-MeOH (100:1, v/v).Removal of solvents afforded 83.5 mg of the titled product (MH+=414).

Preparative Example 20–23.14B

Following the procedures set forth in Preparative Example 19 but usingthe amine from the Preparative Example indicated in the Table below, thecyclobutenedione intermediates were obtained.

Amine from 1. Yield (%) Prep Ex. Prep Ex. Product 2. MH⁺ 20 4

1. 85%2. 333 21 11

1. 44%2. 319 21.1 6

1. 9%2. 291 22 2

1. 38%2. 347 23 14

1. 51%2. 259 23.1 10.1

1. 62%2. 317 23.2 10.2

1. 61%2. 319 23.3 12

1. 40%2. 330 23.4 10.3

1. 42%2. 333 23.5 10.4

1. 40%2. 333 23.6 10.5

1. 37%2. 347 23.7 13.2

1. 39%2. 339 23.8 13.1

1. 42%2. 383/385 23.9 13.19

1. 51%2. 311 23.10 13.20

1. 67%2. 389.1, 390 23.11 13.3

1. 52%2. 383/385 23.12 13.21

1. 76%2. 325.1 23.13 13.22

1. 54% 23.14 13.23

1. 62%2. 378 23.14A 13.70Step B

1. 60%2. 138 23.14B 13.70Step D

1. 65%

Preparative Example 23.15A–23.15F

Following the procedures set forth in Preparative Example 19.2 but usingthe amines from the Preparative Example indicated in the Table below,the corresponding cyclobutenedione intermediates were prepared.

Amine from 1. Yield (%) Prep Ex. Prep Ex. Product 2. MH⁺ 23.15A 13.29

1. 66%2. 347 23.15B 13.30

1. 21%2. 499 23.15C 13.31

1. 41%2. 423 23.15D 13.32

1. 26%2. 437 23.15E 13.33

1. 48%2. 361.1 23.15F   13.32A

1. 68%2. 375.1

Preparative Example 23.16–23.26

Following the procedures set forth in Preparative Example 19 but usingthe amine from the Preparative Example indicated in the Table below, thecyclobutenedione intermediate products were obtained.

Prep Amine from Yield Ex. Prep Ex. Product (%) 23.16 13.11

91% 23.17 13.12

81% 23.18 13.17

47% 23.19 13.27

21% 23.20 13.26

10% 23.21 13.25

49% 23.22 13.13

80% 23.23 13.15

63% 23.24 13.16

64% 23.25 13.17A

48% 23.26 13.17B

66%

Preparative Example 24

Step A

To a solution of N-protected amino acid (1.5 g, 6.9 mmol) in CH₂Cl₂ (25mL) at room temperature was added DIPEA (3.6 mL, 20.7 mmol), and PyBrop(3.4 g, 6.9 mmol) followed by MeNH₂ (6.9 mL, 13.8 mmol, 2.0 M inCH₂Cl₂). The resulting solution was stirred for 18 h at room temperature(until TLC analysis deemed the reaction to be complete). The resultingmixture was washed sequentially with 10% citric acid (3×20 mL), sat. aq.NaHCO₃ (3×20 mL), and brine (3×20 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography eluting with CH₂Cl₂/MeOH(40:1) to afford 1.0 g (63% yield) of a solid.

Step B

To a round bottom charged with the N-protected amide (1.0 g, 4.35 mmol)(from Step A) was added 4N HCl/dioxane (10 mL) and the mixture wasstirred at room temperature for 2 h. The mixture was diluted with Et₂O(20 mL) and concentrated under reduced pressure. The crude product wastreated with Et₂O (2×20 mL) and concentrated under reduced pressure toafford 0.72 g (˜100% yield) of crude product as the HCl salt. Thismaterial was taken on without further purification or characterization.

Preparative Examples 25–33.1

Following the procedure set forth in Preparative Example 24 but usingthe commercially available N-protected amino acids and amines in theTable below, the amine hydrochloride products were obtained.

Prep Ex. Amino acid Amine Product 1. Yield (%) 25

NH₃

1. 70% 26

1. 71% 27

1. 66% 28

1. 65% 29

1. 90% 30

1. 68% 31

1. 68% 32

1. 97% 33

1. 97% 33.1

1. 20%

Preparative Example 33.2

Step A

BOC-valine (45 mg) and PS-carbodiimide (200 mg) were suspended in CH₂Cl₂(4 ml). After addition of the CH₂Cl₂-amine solution (0.138N, 1 ml), themixture was shaken overnight. The solution was filtered and the resinwas washed with more CH₂Cl₂, and the filtrate was concentrated in vacuoto yield the product, which was carried on directly in Step B.

Step B

The crude material from Step A was dissolved in 4N HCl/dioxane (2.5 ml)and stirred for 2 h. The reaction was concentrated in vacuo to yield thedesired amine hydrochloride, which was used directly in the next step.

Preparative Examples 33.3–33.47

Following the procedure set forth in Example 33.2 but using thecommercially available N-protected amino acids in the Table below, theamine hydrochloride products were obtained.

Prep Ex. Amino acid Amine Product 33.3

33.4

33.5

33.6

33.7

33.8

33.9

33.10

33.11

33.12

33.13

33.14

33.15

33.16

33.17

33.18

33.19

33.20

33.21

33.22

33.23

33.24

33.25

33.26

33.27

33.28

33.29

33.30

33.31

33.32

33.33

33.34

33.35

33.36

33.37

33.38

33.39

33.40

33.41

33.42

33.43

33.44

33.45

33.46

33.47

Preparative Example 34

To a solution of 3-chlorobenzaldehyde (2.0 g, 14.2 mmol) in THF (5 mL)at 0° C. was added LiN(TMS)₂ (17.0 ml, 1.0 M in THF) dropwise and theresulting solution was stirred for 20 min. EtMgBr (6.0 mL, 3.0 M inEt₂O) was added dropwise and the mixture was refluxed for 24 h. Themixture was cooled to room temperature, poured into saturated aqueousNH₄Cl (50 mL), and then extracted with CH₂Cl₂ (3×50 volumes). Theorganic layers were combined, concentrated under reduced pressure. Thecrude residue was stirred with 3 M HCl (25 mL) for 30 min and theaqueous layer was extracted with CH₂Cl₂ (3×15 mL) and the organic layerswere discarded. The aqueous layer was cooled to 0° C. and treated withsolid NaOH pellets until pH=10 was attained. The aqueous layer wasextracted with CH₂Cl₂ (3×15 mL) and the organic layers were combined.The organic layer was washed with brine (1×25 mL), dried (Na₂SO₄), andconcentrated under reduced pressure to afford 1.6 g (66% yield) of thecrude amine as an oil (MH⁺ 170). This material was determined to be >90%pure and was used without further purification.

Preparative Example 34.1

The aldehyde (3.5 g) and conc. HCl (20 ml) were combined and stirredovernight at 40° C. The reaction mixture was poured into cold water andextracted with ether, washed with satd. NaHCO₃ and brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give 1.76 g ofproduct (55%)

Preparative Example 34.2

Chlorine was bubbled into 100 ml of CH₂Cl₂ at 10° C. The aldehyde (3.73ml) was charged with 50 ml of CHCl₃ and then cooled to 0° C. AlCl₃ wasadded portionwise, followed by the chlorine solution and let stir atroom temperature overnight. The reaction was poured into 150 ml of iceand 50 ml of 3N HCl and stirred for 30 min. Organic layer was washedwith brine, dried with Na₂SO₄, and concentrated in vacuo. The crudeproduct was purified via flash column chromatography (Hex/EtOAc 40/1) toyield 1.5 g of pure product.

Preparative Example 34.3

Step A

The ketone (3.25 g) was reacted following the procedure set forth inPreparative Example 88.2, Step B to give the oxime (3.5 g, 99%).

Step B

The product from step A (1.2 g) was stirred with AcOH (3 ml) and Pd/C(10%, 300 mg) in EtOH (40 ml) under a hydrogen atmosphere overnight. Thereaction mixture was filtered through celite and the filtrate wasconcentrated in vacuo. The crude material dissolved in ether and washedwith 2N NaOH, organic washed with brine, dried with Na₂SO₄, andconcentrated in vacuo to give product (960 mg, 86%).

Preparative Example 34.4

Step A

To a suspension of NaH (1.45 g) in DMF (25 ml) under a nitrogenatmosphere was added p-bromophenol (5 g) at 0° C. After stirring for 20min, BrCH₂CH(OEt)₂ (5.3 ml) was added and the reaction was heated toreflux overnight. The solution was cooled and poured into ice water (80ml) and extracted with ether. The ether layer was washed with 1N NaOHand brine, dried with MgSO₄, filtered and concentrated in vacuo to give8.4 g of crude product (100%)

Step B

To a solution of the product from Step A (8.4 g) in benzene (50 ml) wasadded polyphosphoric acid (10 g). The mixture was heated at reflux for 4hrs. The reaction was cooled to 0° C. and poured into ice water (80 ml)and extracted with ether. The ether layer was washed with saturatedsodium bicarbonate and brine, dried with MgSO₄, filtered andconcentrated in vacuo to give 4.9 g of crude product (85%)

Step C

To a solution of the product from Step B (2 g) in ether (20 ml) at −78°C. was added t-BuLi dropwise. After stirring for 20 min, DMF (950 mg)was added dropwise and the mixture was stirred at −25° C. for 3 hrs andthen warmed to room temperature overnight. Saturated ammonium chloridewas added and the solution was extracted with ether. The ether layer waswashed with brine, dried with MgSO₄, filtered and concentrated in vacuoto give 980 mg of crude product (67%).

Step D

To a solution of aldehyde (400 g) in ether (10 ml) was added LiN(TMS)₂(1M in THF, 3.3 ml) at 0° C. dropwise. The solution was stirred at 0° C.for 30 min and EtMgBr (3M in THF, 1.83 ml) was added dropwise. Thereaction was refluxed overnight, cooed to 0° C., quenched with saturatedammonium chloride and extracted with ether. The ether was stirred with3N HCl (20 ml), then the aqueous layer was basified with NaOH pelletsand extracted with ether. The ether layer was washed with brine, driedwith MgSO₄, filtered and concentrated in vacuo to give 220 mg of product(46%).

Preparative Example 34.5

Following the procedures set forth in Preparative Example 34.4 Steps Athrough D, but using m-bromophenol (8 g), both amines were formed andseparated by preparative plate chromatography (63–65%, MH+=175).

Preparative Example 34.6

To a solution of 3-methyl-thiophene (5 g) in ether (50 ml) was addeddropwise a solution of n-BuLi (1.6M in hexane, 32 ml). The mixture wasstirred for 1.5 hr at room temperature. DMF (5.1 ml) was then added andlet stir overnight. The mixture was poured into saturated ammoniumchloride and extracted with ether. The ether layer was washed withbrine, dried with Na₂SO₄, and concentrated in vacuo. The crude productwas purified via flash column chromatography (EtOAc/Hex 20:1) to afford5.27 g of an oil (84%).

Preparative Example 34.7

Step A

To a solution of 4-bromo-2-furaldehyde (4 g) in MeOH (75 ml) was addedtrimethyl-orthoformate (3.8 ml). A catalytic amount of p-toluenesulfonic acid (195 mg) and the mixture was heated to reflux for 3.5 hr.The reaction was cooled down and potassium carbonate was added. Themixture was filtered through a silica gel pad. The filtrate wasconcentrated in vacuo, dissolved in CH₂Cl₂ and filtered. The filtratewas again concentrated in vacuo to give 4.03 g of product (80%).

Step B

To a solution of the product from Step A (2.02 g) in THF (80 ml) at −78°C. was added dropwise a solution of n-BuLi (2.5M in hexanes, 4.4 ml) andstirred for 1.5 hr. A solution of iodomethane (1.7 ml) was added and letstir for 2.5 hrs at −60° C. The cooling bath was removed and saturatedammonium chloride was added and let stir for 10 min. The layers wereseparated and the organic layer was washed with brine, dried withNa₂SO₄, and concentrated in vacuo to afford 1.34 g of crude product.

Step C

The product from Step B (1.43 g) was dissolved in acetone (50 ml) andtreated with a catalytic amount of p-toluene sulfonic acid (80 mg). Themixture was heated to reflux for 2 hr. The reaction was cooled down andsolid potassium carbonate was added. The mixture was filtered through asilica gel pad and the filtrate was concentrated in vacuo to give 1.246g of crude product.

Preparative Example 34.8

Step A

To a stirred solution of potassium t-butoxide (2.5 g) in HMPA (20 ml)was added 2-nitropropane (2 ml) dropwise. After 5 min, a solution ofmethyl-5-nitro-2-furoate (3.2 g) in HMPA (8 ml) was added to the mixtureand stirred for 16 hr. Water was added and the aqueous mixture wasextracted with EtOAc. The EtOAc layer was washed with water, dried withMgSO₄, filtered and concentrated in vacuo. The crude material waspurified by flash column chromatography (Hex/EtOAc, 6:1) to yield 3.6 gof product (90%).

Step B

To a solution of the product from Step A (3.6 g) in toluene (16 ml) wasadded tributyltin hydride (5.4 ml) followed by AIBN (555 mg). Themixture was heated to 85° C. for 3.5 hr. After cooling, the mixture wasseparated by flash column chromatography (Hex/EtOAc, 7:1) to afford 2.06g of product (73%).

Step C

To a solution of product from Step B (2.05 g) in THF (60 ml) at 0° C.was added a solution of LAH (1M in ether, 12.8 ml). The reaction wasstirred at room temperature for 30 min. Water and 1M NaOH was addeduntil a precipitate formed, diluted with EtOAc, stirred for 30 min andthen filtered through a celite pad. The organic filtrate wasconcentrated in vacuo to give 1.56 g of product (93%).

Step D

To a solution of product from Step C (2.15 g) in CH₂Cl₂ (100 ml) wasadded Dess-Martin oxidant (7.26 g) in CH₂Cl₂ (45 ml) and stirred for 30min. The mixture was diluted with ether (200 ml). The organic layer waswashed with 1N NaOH, water and brine, dried with MgSO₄, filtered andconcentrated in vacuo to give oil and solid. The material was extractedwith ether and filtered. Some solid crystallized out from the filtrate,filtered again, and the filtrate was concentrated in vacuo to give 2.19g of product.

Preparative Example 34.9

Step A

To a solution of carboxylic acid (5 g) in CH₂Cl₂ (400 ml) at 0° C. wasadded N(OCH₃)CH₃.HCl (11.5 g), DEC (15.1 g), HOBt (5.3 g) and NMM (43ml) and stirred for 14 hr. The mixture was diluted with CH₂Cl₂ (100 ml)and the organic layer was washed with 10% HCl, saturated sodiumbicarbonate and brine, dried with Na₂SO₄, and concentrated in vacuo toafford 5.74 g of crude product (85%).

Step B

To a solution of iodoethane (0.56 ml) in ether (5 ml) at −78° C. wasadded a solution of t-BuLi (1.7M in pentane, 8.3 ml) dropwise. Themixture was warmed to room temperature for 1 hr and transferred to a 100ml round bottom charged with the product from Step A (1 g) in THF (12ml) at −78° C. The mixture was stirred at −78° C. for 1 hr and at 0° C.for an additional 2 hr. 1M HCl was added dropwise followed by CH₂Cl₂.The layers were separated and the organic layer was washed with brine,dried with Na₂SO₄, and concentrated in vacuo to afford 620 mg of product(76%).

Step C

To a solution of the product from Step B (620 mg) in THF/MeOH (10:1) at0° C. was added NaBH₄ (250 mg) in one portion. The mixture was stirredovernight at 0° C., concentrated in vacuo and the crude material wasdissolved in CH₂Cl₂ and washed with 1N NaOH and brine, dried withNa₂SO₄, and concentrated in vacuo to afford 510 mg of product.

Step D

The above material was reacted in the procedures set forth inPreparative Example 75.75 Steps B and C to yield 170 mg of amine product(28%).

Preparative Example 34.10

The above amine was made analogous to the procedures set forth in PatentWO96/22997 p. 56, but using ethylglycine instead of benzylglycine in theDCC coupling.

Preparative Example 34.11

Step A

To the nitro compound (3.14 g) and cyclohexylmethanol (1.14 g) in THF(50 ml) was added PPH₃ (4.72 g) and cooled to 0° C.Diisopropylazadicarboxylate (3.15 ml) was added dropwise and let stirovernight. The reaction was concentrated in vacuo and purified via flashcolumn chromatography (Hex/EtOAc, 30:1) to give product (3.3 g), whichwas carried on directly to the next step.

Step B

To the product from step A (3.3 g) in EtOH (50 ml) was added 10% Pd/C(1.7 g) under a hydrogen atmosphere at 55 psi and let stir overnight.The reaction was filtered through celite and concentrated in vacuo togive 3.2 g of product.

Preparative Example 34.12

Step A

A solution of acid (2 g) in ether (20 ml) was added dropwise to asuspension of LiAlH₄ (350 mg) in ether (15 ml) at 0° C. The solution wasrefluxed for 3 hr and stirred at room temperature ovenright. 5% KOH wasadded and reaction was filtered, extracted with ether, dried with MgSO₄,filtered and concentrated in vacuo to give the product (1.46 g, 79%,MH+=166).

Step B

To a solution of alcohol from above (1.46 g) in CH₂Cl₂ at roomtemperature was added Dess-Martin reagent (5.6 g) portionwise and onedrop of water and let stir over the weekend at room temperature. 10%Na₂S₂O₃ was added and stirred for 20 min, extracted with CH₂Cl₂, washedwith saturated sodium bicarbonate, dried with Na₂SO₄, and concentratedin vacuo to afford 1.1 g of product (76%).

Preparative Example 34.13

The above compound was prepared according to the procedure set forth inEP 0 555 153 A1.

Preparative Example 34.14

The aldehyde (500 mg) from above was reacted following the procedure setforth in the Preparative Example 13.4, Step A to yield 372 mg of product(76%).

Preparative Example 34.15–34.16

Following the procedures set forth in Preparative Example 34.8 but usingthe nitroalkanes indicated in the table below, the aldehydes wereprepared.

Prep. Ex. Nitroalkane Aldehyde Yield 34.15

17% 34.16

21%

Preparative Example 34.17

Step A

To a stirred suspension of 5-bromo-2-furoic acid (15.0 g, 78.54 mmol) in225 mL of CH₂Cl₂ at room temperature was added oxalyl chloride followedby a catalytic amount of N,N′-dimethylforamide. After 1 h, ethanol (20mL) was added followed by triethylamine (22 mL). Reaction was continuedfor 15 h. The mixture was concentrated under reduced pressure to aresidue, which was extracted with excess volume of hexanes, andhexanes-CH₂Cl₂ (3:1, v/v). The extracts were filtered, the filtrated wasconcentrated to a yellow oil, dried on high vacuum, yielding 17.2 g(93%) of the desired ester.

Step B

The ester product obtained from Step A above (17.2 g, 73.18 mmol) wasconverted to 2-ethyl-4-tertbutyl-5-bromo-furoate (7.9 g, 37%) using theliterature procedure: J. Am. Chem. Soc., 1939, 61, 473–478.

Step C

The ester product obtained from Step B above (7.9 g, 27.13 mol) wasreduced to the alcohol (6.32 g) using the procedure set forth inPreparative Example 34.8, Step C.

Step D

The product obtained from Step C above (6.32 g) was dissolved in 140 mLof THF and cooled in a −78° C. bath. A 2.5 M solution of n-butyllithiumin hexanes (22 mL, 55.0 mmol) was added dropwise along the side wall ofthe flask. After 15 min, H₂O (˜70 mL) was added. Cooling bath wasremoved, the mixture was stirred for an additional 1 h. Brine (50 mL)and CH₂Cl₂ (300 mL) were added, the two layers were separated, theaqueous layer was extracted with CH₂Cl₂ (100 mL), and the combinedorganic layers ere dried by Na₂SO₄. Evaporation of solvents afforded5.33 g (crude) of the debrominated product as a reddish brown oil.

Step E

The alcohol product obtained from Step D above (5.33 g) was oxidized tothe corresponding aldehyde (3.06 g, 74% over three steps) using theprocedure set forth in Preparative Example 34.8, Step D.

Preparative Example 34.18

Step A

To a stirred solution of cyclopropyl bromide (4.0 mL, 50 mmol) in 120 mLof ether at −78° C. was added dropwise a 1.7M solution of t-butyllithiumin pentane (44.5 mL, 75.7 mmol). After 10 min, cooling bath was removed,stirring was continued for 1.5 h. The mixture was cooled again in a −78°C. bath, and 3-furaldehyde (3.5 mL, 41.9 mmol) was added. Reaction wascontinued for 1 h, and quenched with a saturated NH4Cl aqueous solution.The aqueous mixture was extracted with CH₂Cl₂ (100 mL×3). The organicextracts were washed with brine, dried by Na₂SO₄, filtered, andconcentrated in vacuo to give 5.3 g (91%) of the alcohol product as ayellow oil.

Step B

Chloro trimethylsilane (27.2 mL, 214.2 mmol) was added dropwise to avigorously stirred suspension of sodium iodide (32 g, 213.5 mmol) in 100mL of acetonitrile. After 5 min, a solution of the alcohol obtained fromStep A above (4.93 g, 35.68 mmol) in 100 mL of acetonitrile was addeddropwise. Stirring was continued for 5 min. H₂O (100 mL) was added, thelayers were separated, and the aqueous layer was extracted with ether(100 mL×2). The organic layers were combined, washed with a 10% Na₂S₂O₃aqueous solution and brine, and dried over Na₂SO₄. Evaporation ofsolvents gave a dark brown oil, which was filtered through a 5-in silicagel column, eluting with CH₂Cl₂-hexanes (1:3.5, v/v). Removal ofsolvents afforded 4.22 g (47%) of the iodo product as a light yellowoil.

Step C

The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) wasdissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 Msolution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was addeddropwise. After 20 min, cooling bath was removed. Reaction was continuedfor 2.5 h, and quenched with H₂O (20 mL). The aqueous mixture wasstirred overnight and separated. The aqueous layer was extracted withether (30 mL). The combined organic layers were washed with brine, driedby Na₂SO₄, and filtered through a Celite pad. Removal of solvent gave1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.

Step D

3-Butylfuran (1.1 g, 8.8 mmol), obtained from Step C above, wasdissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 Msolution of t-butyllithium in pentane (6.0 mL, 10.2 mmol) was addeddropwise along the side wall of the flask. The mixture was stirred for 3h from −78° C. to 0° C., and continued for 1 h at room temperature. Asolution of N,N′-dimethylforamide (1.1 mL, 14.23 mmol) was added.Reaction was continued overnight, and quenched with a saturated NH₄Claqueous solution. The two layers were separated, the aqueous layer wasextracted with CH₂Cl₂ (30 mL×2). The combined organic layers were washedwith brine, dried with Na₂SO₄, and concentrated to an oil, which waspurified by preparative TLC (CH₂Cl₂-hexanes=1:1.5, v/v) to give 0.48 g(36%) of the aldehyde (contaminated by some 3-butyl-2-furaldehyde).

Preparative Example 34.19

Step A

3-Ethylfuran was prepared from 3-hydroxymethylfuran according toliterature procedure: J. Org. Chem., 1983, 48, 1106–1107.

Step B

3-Ethylfuran obtained from Step A above was converted to4-ethyl-2-furaldehyde using the procedure set forth in PreparativeExample 34.32, Step D.

Preparative Examples 35–51.20

Following the procedure set forth in Preparative Example 34 but usingthe commercially available aldehydes and Grignard reagents listed in theTable below, the amine products below were obtained.

Prep Grignard 1. Yield (%) Ex. Aldehyde Reagent Amine 2. MH⁺ 35

EtMgBr

1. 65%2. 154 36

EtMgBr

1. 75%2. 180 37

EtMgBr

1. 78%2. 170 38

EtMgBr

1. 34%2. 204 39

EtMgBr

1. 68%2. 150 40

EtMgBr

1. 40%2. 220 41

EtMgBr

1. 73%2. 154 42

EtMgBr

1. 52%2. 220 43

EtMgBr

1. 55%2. 180 44

EtMgBr

1. 20%2. 204 45

EtMgBr

1. 80%2. 166 46

EtMgBr

1. 35%2. 220 47

i-PrMgBr

1. 20%2. 150 48

EtMgBr

1. 77%2. [M—NH₂]⁺ = 149 49

EtMgBr

1. 77%2. 172 50

EtMgBr

1. 78%2. [M—NH₂]⁺ = 147 51

EtLi

1. 10%2. 116 51.2

EtMgBr

1. 37%2. 161 51.3

EtMgBr

1. 63%2. 216 51.4

EtMgBr

1. 71%2. 228 51.5

EtMgBr

1. 89%2. 168 51.6

EtMgBr

1. 20%2. 228 51.8

EtMgBr

1. 36%2. 222 51.10

1. 95%2. 152.1 51.11

EtMgBr

1. 61%2. 138.1MH⁺—H₂O 51.12

EtMgBr

1. 70%2. 184.1 51.18

EtMgBr

1. 42%2. 147[M—NH₂]⁺ 51.19

EtMgBr

1. 67%2. 204 51.20

EtMgBr

1. 33%2. 188

Preparative Examples 51.25–51.31

Following the procedure set forth in Example 34 but using thecommercially available aldehydes and Grignard reagents listed in theTable below, the amine products were obtained.

Prep Grignard Yield Ex. Aldehyde Reagent Amine (%) 51.25

EtMgBr

20% 51.26

77% 51.27

EtMgBr

51% 51.28

56% 51.29

54% 51.30

EtMgBr

80% 51.31

10%

Preparative Example 52

Step A

A mixture of 2-(trifluoroacetyl)thiophene (2 mL, 15.6 mmol),hydroxylamine hydrochloride (2.2 g, 2 eq), diisopropylethylamine (5.5mL, 2 eq) and MeOH (50 mL) was stirred at reflux for 48–72 hrs, thenconcentrated in vacuo. The residue was diluted with EtOAc, washed with10% KH₂PO₄ and dried over Na₂SO₄ (anhydrous). Filtration andconcentration afforded the desired oxime (2.9 g, 96%) which was useddirectly in Step B without further purification.

Step B

To a mixture of the product from Step A above in TFA (20 mL) was addedZn powder (3 g, 3 eq) portionwise over 30 min and stirred at roomtemperature overnight. The solid was filtered and the mixture reduced invacuo. Aqueous NaOH (2 M) was added and the mixture was extractedseveral times with CH₂Cl₂. The organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated to afford the desired product (1.4 g,50%).

Preparative Examples 53–61

Following the procedure set forth in Preparative Example 52 but usingthe commercially available ketones listed in the Table below, thefollowing amines were obtained.

Prep 1. Yield (%) Example Ketone Amine 2. MH⁺ 53

1. 11%2. 128 54

1. 33%2. 142 55

1. 49%2. 156 56

1. 5%2. 154 57

1. 47%2. 174 58

1. 71%2. 190 59

1. 78%2. 191 60

1. 80%2. 190 61

1. 9%2. 156

Preparative Example 62

To a cooled (0–5° C.) suspension of L-α-(2-thienyl)glycine (0.5 g) andLiBH₄ (2M in THF, 3.8 mL) in anhydrous THF (10 mL) was slowly added aTHF (5 mL) solution of iodine (0.8 g). After stirring at roomtemperature for 15 min, the mixture was stirred at relux overnight.After cooling to room temperature, MeOH was added dropwise until gasevolution ceased and after 30 min, the mixture was evaporated. The oilyresidue was stirred in 20 mL KOH for 4 hrs, diluted with brine andextracted with EtOAc.

The organic phase was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to afford a crude mixture. Purification by flashcolumn chromatography (50% EtOAc/CH₂Cl₂, silica) afforded the product(0.3 g, 63%, MH⁺=144).

Preparative Example 63

CeCl₃-7H₂O was dried at 140–150° C. for 22 hr. To this solid was addedTHF (80 mL, anhydrous) and after stirring for 2 hr, the suspension wascooled to −78° C. and to it was added methyl lithium over 30 min. Afterstirring for an additional 30 min 2-thiophenecarbonitrile dissolved inanhydrous THF (4.5 mL) was added and the resulting mixture stirred foran additional 4.5 hr at −78° C. Concentrated aqueous NH₃ (25 mL) wasadded and the mixture was warmed to room temperature and filteredthrough celite. The filtrate was extracted with dichloromethane, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford acrude mixture. Purification by flash column chromatography (5% MeOH,CH₂Cl₂, silica) afforded the desired product (1.2 g, 62%).

Preparative Example 64

Step A

To a solution of (D)-valinol (4.16 g, 40.3 mmol) in CH₂Cl₂ (60 mL) at 0°C. was added MgSO₄ (20 g) followed by dropwise addition of3-fluorobenzaldehyde (5.0 g, 40.3 mmol). The heterogenous solution wasstirred at 0° C. for 2 h and was allowed to warm to room temperature andstir overnight (14 h). The mixture was filtered and the drying agent waswashed with CH₂Cl₂ (2×10 mL). The filtrate was concentrated underreduced pressure to afford 8.4 g (100%) of an oil which was taken ontothe next step without further purification.

Step B

To a solution of the imine (8.4 g, 40.2 mmol) from Step A in CH₂Cl₂ (60mL) at room temperature was added Et₃N (6.2 mL, 44.5 mmol) followed bydropwise addition of TMSCI (5.7 mL, 44.5 mmol). The mixture was stirredfor 6 h at room temperature whereupon the ppt that had formed wasfiltered off and washed with CH₂Cl₂ (2×10 mL). The combined filtrate wasconcentrated under reduced pressure and was taken up in Et₂O/hexane(1:1/150 mL). The precipitate was filtered off and the filtrate wasconcentrated under reduced pressure to afford 10.1 g (89%) of theprotected imine as an oil. This material was taken onto the next stepwithout further purification.

Step C

To a solution of Etl (4.0 g, 25.6 mmol) in Et₂O (40 mL) at −78° C. wasadded t-BuLi (30.1 mL, 51.2 mmol, 1.7 M in pentane) and the mixture wasstirred for 10 min. The mixture was warmed to room temperature, stirredfor 1 h, and was recooled to −40° C. A solution of the imine (6.0 g,21.4 mmol) from Step B in Et₂O (30 mL) was added dropwise via additionfunnel to afford a bright orange mixture. The reaction mixture wasstirred for 1.5 h at −40° C. then 3M HCl (50 mL) was added and themixture was allowed to warm to room temperature. Water (50 mL) was addedand the layers were separated. The aqueous layer was extracted with Et₂O(2×30 mL) and the organic layers were combined and discarded. Theaqueous layer was cooled to 0° C. and carefully treated with solid NaOHpellets until pH=12 was attained. The aqueous layer was extracted withEt₂O (3×30 mL) and the combined layers were washed with brine (1×30 mL).The organic layer was dried (Na₂SO₄), filtered, and concentrated underreduced pressure to afford 4.8 g (94% yield) of the amine as an oil.This material was taken on crude to the next step without furtherpurification.

Step D

To a solution of amine (4.5 g, 18.8 mmol) from Step C in MeOH (80 mL) atroom temperature was added MeNH₂ (25 mL, 40% in water) followed byaddition of a solution of H₅IO₆ (14.0 g, 61.4 mmol) in H₂O (25 mL). Theheterogenous mixture was stirred for 1.5 h (until the reaction wascomplete by TLC) and the precipitate was filtered off. The resultingfiltrate was diluted with water (50 mL) and the mixture was extractedwith Et₂O (4×60 mL). The combined organic layers were concentrated to avolume of ˜30 mL whereupon 3M HCl (75 mL) was added. The mixture wasstirred overnight (12 h at room temperature) after which the mixture wasconcentrated to remove the volatiles. The aqueous layer was extractedwith Et₂O (3×40 mL) and the organic layers were discarded. The aqueouslayer was cooled to 0° C. and was carefully treated with solid NaOHpellets until pH˜12 was reached. The aqueous layer was extracted withEt₂O (3×60 mL) and the combined organic layers were dried (MgSO₄). Theorganic layer was concentrated under reduced pressure to afford 2.8 g(97% yield) of the desired amine as an oil [MH⁺ 154]. This compound wasproven to be >85% pure by ¹H NMR and was used crude in the subsequentcoupling step.

Preparative Examples 65–75.10J

Following the procedure set forth in Preparative Example 64 but usingthe commercially available aldehydes, amino alcohols, and organolithiumreagents in the Table below, the optically pure amine products in theTable below were obtained.

Prep Amino Organo 1. Yield (%) Ex. Aldehyde Alcohol lithium Product 2.MH⁺ 65

EtLi

1. 62%2. 154 66

EtLi

1. 70%2. 154 67

1. 54%2. 166 68

1. 67%2. 166 69

EtLi

1. 672. 154 70

EtLi

1. 42%2. 142 71

EtLi

1. 36%2. 142 72

1. 62%2. 148 73

t-BuLi

1. 27%2. 256 74

t-BuLi

1. 15%2. 164 75

1. 7%2. 204 75.1

EtLi

1. 65%2. 123[M—NH₂]⁺ 75.2

EtLi

1. 62%2. 123[M—NH₂]⁺ 75.3

EtLi

1. 93%2. 139[M—NH₂]⁺ 75.4

tBuLi

1. 50%2. 167[M—NH₂]⁺ 75.5

tBuLi

1. 48%2. 167[M—NH₂]⁺ 75.6

EtLi

1. 97%2. 139[M—NH₂]⁺ 75.7

iPrLi

1. 872. 153[M—NH₂]⁺ 75.8

1. 94%2. 151[M—NH₂]⁺ 75.9

EtLi

1. 75%2. 151[M—NH₂]⁺ 75.10

tBuLi

1. 30%2. 179[M—NH₂]⁺ 75.10A

1. 61%2. 135[M—NH₂]⁺ 75.10B

EtLi

1. 242. 154 75.10C

EtLi

1. 32%2. 165[M—NH₂]⁺ 75.10D

MeLi

1. 47%2. 137[M—NH₂]⁺ 75.10E

iPrLi

1. 30%2. 165[M—NH₂]⁺ 75.10F

1. 67%2. 163.0[M—NH₂]⁺ 75.10G

EtLi

1. 24%2. 165[M—NH₂]⁺ 75.10H

EtLi

1. 70%2. 194 75.10J

EtLi

1. 54%2. 208

Preparative Examples 75.11–75.59

Following the procedure set forth in Preparative Example 64 but usingthe prepared or commercially available aldehydes, amino alcohols, andorganolithium reagents in the Table below and carrying the amine oncrude, the optically pure amine products in the Table below wereobtained.

Prep Amino Organo Yield Ex. Aldehyde Alcohol lithium Product (%) 75.11

52% 75.12

50% 75.13

iPrLi

57% 75.14

iPrLi

54% 75.15

iPrLi

58% 75.16

61% 75.17

EtLi

72% 75.18

68% 75.19

iPrLi

77% 75.20

t-BuLi

15% 75.21

MeLi

50% 75.22

EtLi

23% 75.24

EtLi

20% 75.27

EtLi

65% 75.28

iPrLi

61% 75.29

EtLi

90% 75.30

iPrLi

62% 75.31

iPrLi

43% 75.32

50% 75.33

50% 75.34

tBuLi

51% 75.35

MeLi

51% 75.36

tBuLi

57% 75.37

tBuLi

60% 75.38

EtLi

73% 75.39

MeLi

48% 75.41

52% 75.42

EtLi

40% 75.43

tBuLi

20% 75.44

t-BuLi

79% 75.45

iPrLi

55% 75.46

tBuLi

39% 75.47

iPrLi

55% 75.48

34% 75.49

EtLi

61% 75.50

tBuLi

25% 75.51

iPrLi

33% 75.52

tBuLi

30% 75.53

EtLi

39% 75.54

38% 75.55

EtLi

64% 75.56

EtLi

46% 75.57

EtLi

62% 75.58

iPrLi

24% 75.59

EtLi

70%

Preparative Example 75.75

Step A

To a solution of aldehyde (2.5 g) in ether (50 ml) at 0° C. was addedEtMgBr (4.56 ml) dropwise. The heterogenous mixture was stirred for 2 hrat 0° C. and then poured into a beaker of saturated ammonium chloride(25 ml), ice and CH₂Cl₂ (30 ml). After the biphasic mixture stirred for10 min, the organic layer was separated, washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to afford the product (2.41g, 95%)

Step B

To a solution of alcohol from Step A above (1 g) in toluene at roomtemperature was added DPPA. The mixture was cooled to 0° C. and DBU wasadded and let stir for 12 hr at room temperature. The layers wereseparated and the organic layer was washed with water, 1N HCl and driedover Na₂SO₄, filtered, and concentrated in vacuo. Purified bypreparative plate chromatography (hexane/EtOAc 20/1) to give the product(840 mg, 75%).

Step C

To a solution of azide (730 mg) from Step B above in THF (7 ml) wasadded PPh₃ (1 g). The heterogenous solution was stirred for 12 hr,whereupon water (1.5 ml) was added. The mixture was refluxed overnight,cooled to room temperature and concentrated in vacuo. Ether and 1N HClwere added to the residue. The aqueous layer was cooled to 0° C.,basified with NaOH pellets and extracted with ether. The ether layer wasdried over MgSO₄, filtered, and concentrated in vacuo to afford theproduct (405 mg, 62%).

Step D

To a solution of azide in THF at −10° C. was added LiAIH₄ portionwise.The heterogenous solution was stirred at room temperature for 1 hr andthen refluxed for 4 hr. The solution was cooled to 0° C. and water, 2MNaOH and ether were added to the reaction. The mixture was filteredthrough a celite pad. The filtrate was treated with 3N HCl. The aqueouslayer was cooled to 0° C., basified with NaOH pellots and extracted withether. The ether layer was dried over MgSO₄, filtered, and concentratedin vacuo to afford the product.

Preparative Example 75.76–75.90

Following a similar procedure set forth in Preparative Example 75.75,and using the reduction procedure indicated, the following amines wereobtained.

Prep Reducing Ex. Aldehyde Step Product % Yield 75.76

D

43% 75.77

C

36% 75.78

D

32% 75.79

C

42% 75.80

D

56% 75.81

D

35% 75.82

C

13% 75.83

C

42% 75.84

C

39% 75.85

C

26% 75.86

C

25% 75.87

C

14% 75.88 (34.14)

C

49% 75.89 (34.13)

C

34% 75.90

C

44%

Preparative Example 76

The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1996, 39, 3319–3323.

Preparative Example 76.1

Step A

To a solution of amine from Preparative Example 75.90 (2.22 g) in CH₂Cl₂(50 ml) at 0° C. was added TEA (3.03 ml) followed by BOC₂O (2.85 g). Theheterogenous mixture was allowed to stir at room temperature overnight.10% Citric acid was added to the reaction and the layers were separated.The organic layer was washed with saturated sodium bicarbonate, brineand dried with Na₂SO₄, filtered, and concentrated in vacuo. The crudematerial was purified by flash column chromatography (Hex/EtOAc 10:1) toafford 2.7 g of an oil (81%).

Step B

Following the procedure from Preparative Example 13.4, Step A, but usingthe product from Step A above (450 mg) and 3-thiophene boronic acid (284mg), the product was prepared (325 mg, 71%).

Step C

To the product from Step B (325 g) was added 4M HCl in dioxane (1.31 ml)and let stir for 1 hr. The reaction was concentrated in vacuo and takenup in CH₂Cl₂ and concentrated in vacuo again. This procedure wasrepeated 5 times to afford a semisolid (89%).

Preparative Example 76.2–76.3

Following the procedures set forth in Preparative Example 76.1, butusing the commercially available boronic acids, the indicated amineswere prepared.

Prep Ex. Boronic Acid Product Yield (%) 76.2

70% 76.3

35%

Preparative Example 76.10

Step A

The product from Preparative Example 75.75, Step A (2.5 g) was reactedvia the Preparative Example 13.11, Step B to give the ketone (1.93 g,78%).

Step B

To a solution of ketone from Step A above (500 mg) in THF (5 ml) at 0°C. was added S-2-methyl-CBS-oxazaborolidine (0.98 ml) dropwise followedby BH₃.Me₂S (1.48 ml). The mixture was stirred at 0° C. for 2 hr and wasallowed to warm to room temperature and stir overnight. The mixture wascooled to 0° C. and treated with MeOH (10 ml). After stirring for 20min, the reaction was concentrated in vacuo. The residue was dissolvedin CH₂Cl₂ and washed with 1M HCl, saturated sodium bicarbonate, waterand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude material was purified by preparative plate chromatography(Hex/EtOAc 4:1) to afford 650 mg of an oil (89%).

Step C

The chiral alcohol from Step B above was reacted via the PreparativeExample 75.75 Step B to give the azide.

Step D

The azide from Step C above was reacted via the Preparative Example75.75 Step C to give the amine product.

Preparative Example 76.11

The desired compound was prepared as in Preparative Example 76.10, butusing the R-2-methyl-CBS-oxazaborolidine in step B.

Preparative Example 77

The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1996, 39, 3319–3323.

Preparative Example 78

The desired compound was prepared according to methods previouslydescribed in Chem. Pharm. Bull. 1991, 39, 181–183.

Preparative Example 78.1

The desired compound was prepared according to methods previouslydescribed in J. Organometallic Chem. 1998, 567, 31–37.

Preparative Example 79

The desired compound was prepared according to methods previouslydescribed in Chem. Pharm. Bull. 1991, 39, 181–183.

Preparative Example 80

The desired compound was prepared according to methods previouslydescribed in a) Synthesis 1987, 998–1001, b) Synthesis 1996, 641–646 andc) J. Med. Chem. 1991, 34, 2176–2186.

Preparative Example 81

The desired compound was prepared according to methods previouslydescribed in a) Synthesis 1987, 998–1001, b) Synthesis 1996, 641–646 andc) J. Med. Chem. 1991, 34, 2176–2186.

Preparative Example 82

The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1988, 31, 2176–2186.

Preparative Example 83

To a solution of carboxylic acid (1.5 g, 7.89 mmol) in H₂O/acetone(1:10/12 mL total) at 0° C. was added Et₃N (1.43 mL, 10.3 mmol) followedby addition of ethyl chloroformate (0.83 mL, 8.68 mmol). The resultingmixture was stirred for 30 min after which a solution of NaN₃ (0.77 g,11.8 mmol) in H₂O (2 mL) was added dropwise. The resultant heterogenousmixture was stirred for 1 h at 0° C., then cold water (5 mL) and Et₂O(10 mL) were added. The layers were separated and the aqueous layer wasextracted with Et₂O (2×10 mL). The organic layers were combined, toluene(20 mL) was added, and the organic layers were dried (MgSO₄) andconcentrated under reduced pressure to a volume of 20 mL. t-BuOH (5 mL)was added and the mixture was refluxed for 12 h. The mixture wasconcentrated under reduced pressure and the crude residue was taken upin 3M HCl (30 mL) and was heated at reflux for 12 h. The mixture wascooled to room temperature and extracted with Et₂O (3×15 mL). Theaqueous layer was cooled to 0° C. and solid NaOH pellets were addeduntil pH˜12 was reached. The aqueous layer was extracted with Et₂O (3×30mL) and the combined organic layers were dried (MgSO₄) and concentratedunder reduced pressure to afford 0.78 g (61% yield) of an oil [MH⁺ 162].This material was used without further purification.

Preparative Example 84

The corresponding cyclopropyl analog was prepared according to theprocedure outlined in Preparative Example 83.

Preparative Example 85

The corresponding cyclohexyl analog was prepared according to theprocedure outlined in Preparative Example 83.

Preparative Example 86

The desired compound was prepared according to methods previouslydescribed in J. Org. Chem. 1978, 43, 892–898.

Preparative Example 87

A mixture of (R)-(+)phenylpropanolamine (8.2 g),3,4-diethoxy-3-cyclobutene-1,2-dione (10 g) and absolute EtOH (75 mL)was stirred at 0–25° C. for 12 hrs. Filtration and concentration of thefiltrate gave a syrup which was chilled in the freezer to give a solid.Trituration of the solid with diethyl ether gave the desired product(10.5 g, 71%, MH⁺=260).

Preparative Example 87.1

(R)-1-phenyl propylamine (4.82 ml) and3,4-dimethoxy-3-cylclobutene-1,2-dione (5.03 g) were combined in MeOH(40 ml) and stirred overnight. Reaction concentrated in vacuo andpurified via flash column chromatography (MeOH/CH₂Cl₂, 1:40) to yield2.75 g of product (31%, MH+=246).

Preparative Example 88

A mixture of (S)-(+)-3-methyl-2-butylamine (3.0 g),3,4-diethoxy-3-cyclobutene-1,2-dione (5 g) and absolute EtOH (100 mL)was stirred at 0–25° C. for 12 hrs. Filtration and concentration of thefiltrate gave a syrup which solidified upon dilution with Et₂O.Trituration of the solid with diethyl ether gave the desired product asa solid (4.4 g, 72%, MH⁺=212).

Preparative Example 88.1

A mixture of amine from Preparative Example 75.1 (370 mg),3,4-diethoxy-3-cyclobutene-1,2-dione (0.39 ml) and absolute EtOH (5 ml)was stirred at room temperature overnight. Purification by preparativeplate chromatography (3% EtOH/CH₂Cl₂) afforded the desired product (263mg, 37%).

Preparative Example 88.2

Step A

2-Methylthiophene (3 g) was dissolved in THF and cooled to −40° C.N-butyllithium (2.5M in hexane, 12.24 ml) added dropwise and let stir at−40° C. for 30 min. CuBr.(CH₃)₂S (6.29 g) added and let warm to −25° C.where the trifluoroaceticanhydride (4.32 ml) was added. The reaction wasstirred at −15° C. over the weekend. The reaction was quenched withsaturated ammonium chloride and extracted with EtOAc. The organic layerwashed with brine, dried with MgSO₄, filtered and concentrated in vacuoto give 4.59 g of an oil (78%).

Step B

The product from Step A (4.58 g), hydroxylamine hydrochloride (3 g),sodium acetate (4.4 g), EtOH (75 ml) and H₂O (7.5 ml) were combined andheated to 75° C. overnight. The reaction was concentrated in vacuo,taken up 1N HCl, extracted with ether, dried with MgSO₄, filtered andconcentrated in vacuo to give 4.58 g of the product (93%, MH+=210).

Step C

The product from Step B above (4.5 g) was dissolved in TFA (40 ml) andcooled to 0° C. Zn powder (4.2 g) was added portionwise and let reactionwarm to room temperature and stir overnight. The reaction wasconcentrated in vacuo, taken up in 1N NaOH, extracted with ether, driedwith MgSO₄, filtered and concentrated in vacuo to give 3.43 g of theproduct (80%).

Step D

The product from Step C (526 mg), 3,4-diethoxy-3-cyclobutene-1,2-dione(0.4 ml) and absolute EtOH (10 ml) was stirred at room temperatureovernight. Purification by preparative plate chromatography (10%EtOAc/Hex) to give 178 mg of product (21%, MH+=320).

Preparative Example 88.3

Following a similar procedure as described in Preparative Example 88.2,but instead using 2-methylfuran, the above cyclobutenedione intermediatewas prepared.

Preparative Example 88.4

The amine from Preparative Example 75.1 (973 mg) and thedimethoxysquarate (870 mg) were dissolved in MeOH (20 ml) and stirredfor 3 days. The reaction was concentrated in vacuo and purified viaflash column chromatography (MeOH/CH₂Cl₂, 1%) to yield 325 mg of product(19%, MH+=249.8).

Preparative Example 88.5

The amine from Preparative Example 75.9 (323 mg) and thedimethoxysquarate (426 mg) were dissolved in MeOH (10 ml) and stirredover the weekend. The reaction was concentrated in vacuo and purifiedvia flash column chromatography (MeOH/CH₂Cl₂, 1:20) to yield 407 mg ofproduct (57%, MH+=235.8).

Preparative Example 89

To a solution of KH (0.45 g, 11.3 mmol) in THF (15 mL) at roomtemperature was added amine hydrochloride (0.85 g, 5.1 mmol) portionwiseto afford a heterogenous reaction mixture. The mixture was allowed tostand overnight (12 h) and Mel (0.32 mL, 5.1 mmol) was added dropwise.The mixture was stirred for 6 h after which the mixture was carefullypoured into cold brine (125 mL). The mixture was extracted with Et₂O(3×25 mL) and the organic layers were combined. The organic layer wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford the crude product as an oil. This material was carried on crudeto the coupling step without further purification or characterization.

Preparative Example 89.1

To a solution of KH (1.1 g) in THF (20 ml) at room temperature was added(R)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenous mixture.The mixture was allowed to stand overnight (18 hr) and then Mel (1.59ml) was added dropwise. The mixture was stirred for 4 hr after whichbrine was added. Extracted with ether, dried with K₂CO₃, filtered andconcentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 89.2

To a solution of KH (1.1 g) in THF (20 ml) at room temperature was added(S)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenous mixture.The mixture was allowed to stand overnight (18 hr) and then Mel (1.59ml) was added dropwise. The mixture was stirred for 4 hr after whichbrine was added. Extracted with ether, dried with K₂CO₃, filtered andconcentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 90

The corresponding cis analog was prepared in an analogous fashionutilizing the procedure described in Preparative Example 89. Thismaterial was also used without further purification.

Preparative Example 91

The desired compound was prepared according to methods previouslydescribed in J. Org. Chem. 1987, 52, 4437–4444.

Preparative Example 92

The desired compound was prepared according to methods previouslydescribed in Bull. Chem. Soc. Jpn. 1962, 35, 11–16.

Preparative Example 93

The desired amine was prepared from the corresponding ketone accordingto standard methods previously described in a) Synthesis 1987, 998–1001,b) Synthesis 1996, 641–646 and c) J. Med. Chem. 1991, 34, 2176–2186.

Preparative Example 94

The desired amine was prepared from the corresponding ketone accordingto standard methods previously described in a) Synthesis 1987, 998–1001,b) Synthesis 1996, 641–646 and c) J. Med. Chem. 1991, 34, 2176–2186.

Preparative Example 95

Step A

Lithium hexamethyldisilylazide (34 mL, 1M in THF) was added dropwise toa −78° C. THF (20 mL) solution of isobutyronitrile (2.8 mL). After 40min, cyclopropylmethylbromide (5 g) was added and the mixture warmed toand stirred at 25° C. overnight. After cooling to 0° C., 1M HCl (aq) wasadded and the mixture was extracted with diethyl ether, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo at 0° C. to givethe desired product (4.5 g).

Step B

Methyl Lithium (17 mL, 1.4 M in Et₂O) was added to the product from StepA above (1.5 g) in Et₂O (anhydrous) at 0° C. The mixture was stirred at0–25° C. overnight, then diluted with 3M HCl (aq), extracted withCH₂Cl₂, dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo at0° C. and used directly in Step C.

Step C

The product from Step B above was added to a slurry of NaBH₄ (1.4 g) inisopropanol (50 mL) at 0° C., then the mixture was stirred at reflux for8 hr and at room temperature for 48 hrs. Water was added and the mixturewas stirred for 30 min, then extracted with diethyl ether, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue wasdiluted with CH₂Cl₂ and extracted with 3M HCl. The organic phase wasdiscarded and the aqueous phase was basified with NaOH (aq) andextracted with CH₂Cl₂. Drying over anhydrous Na₂SO₄, filtering, andconcentration in vacuo gave the desired compound (0.5 g).

Preparative Example 96

Step A

2-Thiophenecarbonyl chloride (2.0 mL, 18.7 mmol) was dissolved in 100 mLdichloromethane. After addition of diisopropylethylamine (4.1 mL, 23.4mmol) and Boc-piperazine (3.66 g, 19.7 mmol), the mixture was stirredfor 4 h at room temperature. The resulting mixture was put into water(500 mL) and acidified with 3N HCl to pH˜1. Extraction withdichloromethane (2×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in the next step without anyfurther purification.

¹H NMR (300 MHz, d₆-DMSO) 1.60 (s, 9H), 3.29 (dd, 4H), 3.69 (dd, 4H),7.23 (dd, 1H), 7.49 (d, 1 H), 7.79 (d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 2 h, the reactionmixture was put into 1N sodium hydroxide (400 mL). Extraction withdichloromethane (2×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.81 (dd, 4H), 3.63 (dd, 4H),7.21 (dd, 1H), 7.46 (d, 1H), 7.82 (d, 1H).

Step C

The crude material (3.50 g, 17.8 mmol) from Step B was dissolved indichloromethane (100 mL). After addition of diisopropylethylamine (18.7mL, 107 mmol), 3-nitrosalicylic acid (3.3 g, 18.0 mmol), and PyBrOP(10.4 g, 22.3 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (200 mL).Extraction with dichloromethane (2×200 mL) removed all PyBrOPby-products. The aqueous phase was acidified with 3N HCl andsubsequently extracted with dichloromethane (3×100 mL). The combinedorganic phases of the acidic extraction were dried over sodium sulfate,concentrated, and finally purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (2.31 g,34% over 3 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.30–3.90 (m, 8H),7.10–8.20 (m, double signals due to E/Z-isomers, 6H), 10.82 (s, 1H).

Step D

The nitro-compound (2.3 g, 6.4 mmol) from Step C was dissolved inmethanol (50 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (1.78 g,84%). ¹H NMR (300 MHz, d₆-DMSO) 3.30–3.90 (m, 8H), 7.22 (m, 2H), 7.55(d, 1H), 7.71 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 10.85 (bs, 1H).

Preparative Example 97

Step A

Picolinic acid (3.0 g, 24.3 mmol) was suspended in SOCl₂ (15 mL). Afteraddition of dimethylformamide (5 drops), the reaction mixture wasstirred for 4 hours. Evaporation of the solvent yielded thecorresponding acid chloride as HCl-salt. Without any furtherpurification, the solid was suspended in 120 mL dichloromethane. Afteraddition of diisopropylethylamine (12.7 mL, 73 mmol) and Boc-piparazine(4.8 g, 25.5 mmol), the reaction was stirred over night at roomtemperature. The resulting mixture was put into water (500 mL) andextracted with dichloromethane (2×100 mL). Drying over sodium sulfateresulted in sufficiently pure product that was used in Step B withoutany further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.63 (s, 9H), 3.21(dd, 4H), 3.61 (dd, 4H), 7.57 (dd, 1H), 7.63 (d, 1H), 7.98 (dd, 1H),8.70 (d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 2 days, thereaction mixture was put into 1N sodium hydroxide (400 mL). Extractionwith dichloromethane (2>100 mL) and drying over sodium sulfate resultedin sufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.77 (dd, 2H), 2.83 (dd, 1H),3.38 (dd, 2H), 3.64 (dd, 1H), 7.58 (dd, 1H), 7.62 (d, 1H), 8.00 (dd,1H), 8.67 (d, 1H).

Step C

The crude material (1.35 g, 7.06 mmol) from Step B was dissolved indichloromethane (50 mL). After addition of diisopropylethylamine (3.7mL, 21.2 mmol), 3-nitrosalicylic acid (1.36 g, 7.41 mmol), and PyBrOP(3.62 g, 7.77 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (300 mL).Extraction with dichloromethane (2×100 mL) removed any PyBrOP products.The aqueous phase was acidified with 3N HCl. Adjustment of the pH withsaturated sodium carbonate solution to almost neutral crushed thedesired compound out of solution. The aqueous phase was subsequentlyextracted with dichloromethane (3×100 mL). The combined organic layersof the neutral extraction were dried over sodium sulfate, concentrated,and finally purified by column chromatography(dichloromethane/methanol=20/1) to yield the desired product (1.35 g,16% over 3 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.30–3.95 (m, 8H), 7.22 (m,1H), 7.61 (m, 1H), 7.73 (d, 2H), 8.03 (m, 1H), 8.17 (m, 1H), 8.69 (m,1H), 10.82 (s, 1H).

Step D

The nitro-compound (1.35 g, 3.79 mmol) from Step C was dissolved inmethanol (60 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol=20/1) to yield the desired product (1.10 g,89%).

¹H NMR (300 MHz, d₆-DMSO) 3.50–3.85 (m, 8H), 6.47 (dd 1H), 6.74 (m, 2H),7.59 (dd, 1H), 7.71 (d, 1H), 8.04 (dd, 1H), 8.68 (d, 1H).

Preparative Example 98

Step A

1-Methyl-2-pyrrolecarboxylic acid (2.5 g, 20.0 mmol) was dissolved indichloromethane (50 mL). After addition of PyBrOP (16.3g. 35.0 mmol),diisopropylethylamine (14.0 mL, 73.0 mmol) and Boc-piparazine (5.5 g,30.0 mmol), the reaction was stirred over night at room temperaturebefore being put into 1N sodium hydroxide (200 mL). Extraction withdichloromethane (2×100 ml) removed all PyBrOP by-products. The aqueousphase was acidified with 3N HCl. Adjustment of the pH with saturatedsodium carbonate solution to almost neutral precipitated the desiredcompound. The aqueous phase was subsequently extracted withdichloromethane (3×100 mL). The combined organic phases of the neutralextraction were dried over sodium sulfate. Removal of the solventresulted in sufficiently pure product that was used in Step B withoutany further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.59 (s, 9H) 3.21(dd, 4H), 3.61 (dd, 4H), 3.74 (s, 3H), 6.11 (dd, 1H), 6.33 (d, 1H), 7.01(d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 3 h, the reactionmixture was put into 1N sodium hydroxide (400 mL). Extraction withdichloromethane (3×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.79 (dd, 4H), 3.62 (dd, 4H),3.76 (s, 3H), 6.11 (dd, 1H), 6.37 (d, 1H), 6.96 (d, 1H).

Step C

The crude material (3.15 g, 16.3 mmol) from Step B was dissolved indichloromethane (100 mL). After addition of diisopropylethylamine (8.5mL, 49.0 mmol), 3-nitrosalicylic acid (3.13 g, 17.1 mmol), and PyBrOP(9.11 g, 19.6 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (400 mL).Extraction with dichloromethane (2×100 mL) removed all PyBrOP products.The aqueous phase was then carefully acidified with 3N HCl until thecolor of the solution changes from orange to yellow and the desiredcompound crashed out of solution. The aqueous phase was subsequentlyextracted with dichloromethane (3×100 ml). The combined organic layersof the acidic extraction were dried over sodium sulfate and concentratedin vacuo to yield the desired product. ¹H NMR (300 MHz, d₆-DMSO)3.35–3.85 (m, 8H), 3.79 (s, 3H), 6.13 (dd, 1H), 6.45 (d, 1H), 7.01 (s,1H), 7.22 (dd, 1H), 7.70 (d, 1H), 8.16 (d, 1H), 10.83 (s, 2H).

Step D

The crude nitro-compound from Step C was suspended in methanol (60 mL)and stirred with 10% Pd/C under a hydrogen gas atmosphere over night.The reaction mixture was filtered through Celite and washed thoroughlywith methanol. The filtrate was concentrated in vacuo and purified bycolumn chromatography (dichloromethane/methanol=10/1) to yield thedesired product (2.61 g, 40% for 4 steps). ¹H NMR (300 MHz, d₆-DMSO)3.45–4.80 (m, 8H), 3.79 (s, 3H), 6.17 (dd, 1H), 6.45 (m, 2H), 6.78 (m,2H), 7.01 (d, 1H).

Preparative Example 99

Step A

2-Bromopyridine N-oxide hydrochloride (1.13 g, 5.37 mmol) andBoc-piperazine (1.50 g, 8.06 mmol) were heated to 80° C. in pyridine (10mL) over night. The reaction mixture was put into water (300 mL) andthen extracted with dichloromethane (2×100 mL). The combined organicphases were dried over sodium sulfate, concentrated, and finallypurified by column chromatography (dichloromethane/methanol=10/1) toyield the desired product (500 mg, 33%).

¹H NMR (300 MHz, d-CDCl₃) 1.60 (s, 9H), 3.46 (dd, 4H), 3.78 (dd, 4H),6.99 (m, 2H), 7.37 (dd, 1H), 8.33 (d, 1H).

Step B

The purified product (500 mg, 1.79 mmol) was stirred for 30 min with 4NHCl/dioxane (15 mL). Evaporation of the solvent yielded the crude amine(465 mg) as multiple HCl-salt which was used in Step C without anyfurther purification.

¹H NMR (300 MHz, d₆-DMSO) 3.38 (m, 4H), 4.81 (m, 4H), 7.34 (dd, 1H),7.55 (d, 1H), 7.86 (dd, 1H), 8.55 (d, 1H).

Step C

The crude material (370 mg, 1.48 mmol) from Step B was suspended indichloromethane (20 mL). After addition of diisopropylethylamine (2.6mL, 14.8 mmol), 3-nitrosalicylic acid (406 mg, 2.22 mmol), and PyBrOP(1.21 g, 2.59 mmol), the mixture was stirred over night at roomtemperature before being put into 1N sodium hydroxide (50 mL).Extraction with dichloromethane (2×50 mL) removed all PyBrOP products.The aqueous phase was then carefully acidified (pH˜4–5) with 3N HCl andextracted with dichloromethane (3×50 mL). The combined organic layers ofthe acidic extraction were dried over sodium sulfate, concentrated invacuo and purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (330 mg,65%).

LCMS calculated: 344.1. found: (M+1)⁺ 345.1.

Step D

Sodium hydrosulfite (1.05 g) was dissolved in water (3.0 mL) to yield a1.5N solution. Addition of dioxane (3.0 mL) was followed by injection ofconc. ammonium hydroxide (0.60 mL, yields a 1.0N concentration). Afteraddition of the nitro-compound (100 mg, 0.29 mmol), the reaction mixturewas stirred for 0.5 h. Subsequently, the solvent was removed and theresidue suspended in dichloromethane/methanol (10/1). Filtration throughCelite removed most of the salts. Final purification by columnchromatography (dichloromethane/methanol=5/1) yielded the desiredproduct (68 mg, 75%).

LCMS calculated: 314.14. found: (M+1)⁺ 315.1.

Preparative Example 100

Step A

4-Bromopyridine hydrochloride (3.0 g, 15.4 mmol) was dissolved in water(15 mL). After addition of N-benzylpiperazine (14.8 mL, 85.0 mmol) and500 mg copper sulfate, the reaction mixture was heated overnight to 140°C. The resulting product was extracted with ether (5×75 mL), dried oversodium sulfate and concentrated. Final purification by columnchromatography (dichloromethane/methanol/NH₄OH=10/1/0.1) yielded thedesired product (2.16 g, 55%). ¹H NMR (300 MHz, d-CDCl₃) 2.68 (dd, 4H),3.45 (dd, 4H), 6.76 (d, 2H), 7.40 (m, 5H), 8.38 (d, 2H).

Step B

The benzylamine (2.16 g, 8.54 mmol) from Step A, ammonium formate (2.71g, 43.0 mmol) and Pd(C) (10%, 1.0 g) was suspended in methanol (50 mL)and refluxed for 3 h. The palladium was filtered off and the filtratewas concentrated. The sufficiently pure product was used in Step Cwithout any further purification. ¹H NMR (300 MHz, d-CDCl₃) 2.48 (bs,1H), 3.13 (dd, 4H), 3.41 (dd, 4H), 7.78 (d, 2H), 8.39 (d, 2H).

Step C

The crude material (1.15 g, 7.06 mmol) from Step B was dissolved indichloromethane (50 mL). After addition of diisopropylethylamine (4.7mL, 42.4 mmol), 3-nitrosalicylic acid (1.94 g, 10.6 mmol), and PyBrOP(5.78 g, 12.3 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (300 mL).Extraction with dichloromethane (2×100 mL) removed all PyBrOP products.The aqueous phase was carefully acidified to pH˜5–6 with 3N HCl andextracted with dichloromethane (3×100 mL). The combined organic layersof the neutral extraction were dried over sodium sulfate, concentrated,and finally purified by column chromatography(dichloromethane/methanol/NH₄OH=10/1/0.1) to yield the desired product(850 mg, 37% for 2 steps).

Step D

The nitro-compound (850 mg, 2.59 mmol) from Step C was dissolved inmethanol (40 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol/NH₄OH=10/1/0.1) to yield the desired product(650 g, 84%). ¹H NMR (300 MHz, d₆-DMSO) 3.40–3.75 (bm, 8H), 6.49 (dd,1H), 6.76 (m, 2H), 6.93 (d, 2H), 8.28 (d, 2H).

Preparative Example 101

Step 1

N,N′-Dibenzyl-ethane-1,2-diamine (20 mL, 0.0813 mol), triethylamine(22.66 mL, 0.1626 mol) and benzene (100 mL) were combined in a roundbottom flask. A solution of 2,3-dibromo-propionic acid ethyl ester(11.82 mL, 0.0813 mol) in benzene (50 mL) was added dropwise. Thesolution was refluxed over night and monitored by TLC (20% ethylacetate/hexane). The reaction was cooled to room temperature, thenfiltered and washed with benzene. The filtrate was concentrated thenpurified by column chromatography (15% ethyl acetate/hexane). Theproduct was isolated as an oil (25.42 g, 0.0752 mol, 92%). MS:calculated: 338.20. found: 339.2.

¹H NMR (300 MHz, CDCl₃) 1.23 (t, 3H), 2.48 (m, 3H), 2.62 (m, 1H), 2.73(m, 1H), 3.07 (m, 1H), 3.30 (m, 1H), 3.42 (d, 1H), 3.56 (m, 2H), 3.91(d, 1H), 4.17 (m, 2H) , 7.27 (m, 10H).

Step 2

In a Parr shaker vessel, the ester (25.43 g, 0.075 mol) and methanol(125 mL) were combined. The vessel was purged with argon and palladiumcatalyst (5% on carbon, 2.5 g) was added. The system was shaken under anatmosphere of hydrogen overnight. TLC (20% ethyl acetate/hexane)indicated that reaction was complete. The reaction mixture was filteredthrough a pad of Celite and washed with methanol. The filtrate wasconcentrated and the product isolated as a solid (11.7 g, 0.074 mol,98%).

MS: calculated: 158.11. found:159.2 ¹H NMR (300 MHz, CDCl₃) 1.27 (t,3H), 2.70 (m, 4H), 2.96 (m, 1H), 3.13 (dd, 1H), 3.43 (dd, 1H), 4.18 (m,2H).

Preparative Example 102

Piperazine-2-carboxylic acid ethyl ester (3.11 g, 0.0197 mol),diisopropylethylamine (5.15 mL, 0.0296 mol) and methylene chloride (200mL) were combined in a round bottom flask. While stirring at roomtemperature, a solution of N,N-dimethylcarbamoyl chloride (1.81 mL,0.0197 mol) in methylene chloride (20 mL) was added dropwise. Thereaction was stirred for one hour. After this time the reaction wasconcentrated and carried on to the next step without furtherpurification. (99% yield).

MS: calculated: 229.14. found: 230.1. ¹H NMR (300 MHz, CDCl₃) 1.30 (t,3H), 2.85 (s, 6H), 3.10 (m, 3H), 3.31 (m, 2H), 3.60 (m, 2H), 4.21 (q,2H).

Preparative Example 103–104

Following the procedure described for Example 102, the Products listedin the table below were prepared using the commercially availablechloride shown and piperazine-2-carboxylic acid ethyl ester fromPreparative Example 101.

1. Yield (%) Example Chloride Product 2. (M + 1)⁺ 103

1. 99%2. 237.1 104

1. 62%2. 253.1

Preparative Example 105

Step 1

3-Nitrosalicylic acid (3.61 g, 0.0197 g), DCC (2.03 g, 0.0099 mol) andethyl acetate (130 mL) were combined in a round bottom flask and stirredfor 15 min. 4-Dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester(4.51 g, 0.0197 g) was added, and the reaction was stirred for 72 hours.The reaction mixture was concentrated then dissolved in dichloromethane.The organic phase was washed once with 0.1N sodium hydroxide. Theaqueous phase was back extracted once with dichloromethane. The aqueousphase was acidified and wash three times with ethyl acetate. The aqueousphase was concentrated and purified by column chromatography (5%methanol/DCM).

MS: calculated: 394.15. found: 395.0. ¹H NMR (300 MHz, CDCl₃) 1.32 (t,3H), 2.86 (m, 7H), 3.15 (m, 1H), 3.51 (m, 4H), 4.24 (m, 3H), 7.15 (m,1H), 7.66 (m, 1H), 8.20 (m, 1H), 10.86 (bs, 1H).

Step 2

4-Dimethylcarbamoyl-1-(2-hydroxy-3-nitro-benzoyl)-piperazine-2-carboxylicacid ethyl ester (0.80 g, 0.002 mol) and methanol (50 mL) were combinedin a round bottom flask. The system was purged with argon. To thesolution was added 5% palladium on carbon (˜100 mg). The flask waspurged with hydrogen and stirred overnight. The reaction was filteredthrough a pad of celite and washed with methanol. The material wasconcentrated then purified by column chromatography (6% methanol/DCM).Isolated product (0.74 g, 0.002 mol, 100%).

MS: calculated: 364.17. found: 365.1. ¹H NMR (300 MHz, CDCl₃) 1.27 (t,3H), 2.85 (m, 8H), 3.18 (1H), 3.45 (m, 3H), 4.19 (m, 3H), 3.90 (m, 3H)

Step 3

1-(3-Amino-2-hydroxy-benzoyl)-4-dimethylcarbamoyl-piperazine-2-carboxylicacid ethyl ester (0.74 g, 0.002 mol) was suspended in a solution ofdioxane (10 mL) and water (10 mL). Lithium hydroxide (0.26 g, 0.006 mol)was added and the mixture stirred for two hours. The solution wasacidified to pH=6 with 3N HCl then extracted with butanol. The extractswere combined, dried over sodium sulfate and concentrated.

MS: calculated: 336.14. found: 337.1. ¹H NMR (300 MHz, CD₃OD) 2.86 (m,7H), 3.23 (m, 3H), 3.54 (m, 3H), 6.92 (m, 2H), 7.23 (m, 1H).

Preparative Example 106–107

Following the procedure described for Example 105, the Products listedin the table below were prepared using the amine from the PreparativeExample indicated and 3-nitrosalacylic acid.

1. Yield (%) 2. (M + 1)⁺ Example Aniline Product 3. Note 106 103

1. 91%2. Not observed3. Rainey nickelused in Step 2 107 104

1. 24%2. 360.03. For Step 1used PyBrop/DIEA in DCM

Preparative Example 108

Step A

3-Nitrosalicylic acid (1.0 g, 5.5 mmol) was dissolved in ethyl acetate(20 mL). 1,3-Dicyclohexylcarbodiimide (0.568 g, 2.8 mmol) was added andthe mixture was stirred for approximately 10 minutes and cooled to 0° C.During this time a precipitate formed. Azetidine (0.39 mL, 5.8 mmol) wasadded and the reaction was stirred overnight and allowed to warm to roomtemperature. After this time the reaction was cooled to 0° C. andfiltered. The collected solid was washed with chilled ethyl acetate. Thefiltrate was concentrated and purified by column chromatography (80%EtOAc/Hex) to give the product (476 mg, 39.0%).

¹H NMR (300 MHz, CDCl₃) δ2.40(m, 2H), 4.38(m, 4H), 6.97(m, 1H), 7.62(d,1H), 8.12(d, 1H), 12.88(m, 1H) ppm.

The nitro compound (0.48 g, 2.1 mmol) from Preparative Example 32 Step Awas dissolved in methanol (25 ml) and stirred with 10% Pd/C under ahydrogen gas atmosphere overnight. The reaction mixture was filteredthrough celite, the filtrate concentrated in vacuo to give the product(344 mg, 90%). ¹H NMR (300 MHz, CDCl₃) δ2.52(m, 2H), 4.57(bs, 4H),6.75(m, 1H), 6.90(m, 2H), 12.71(bs, 1H) ppm.

Preparative Example 109

In essentially the same manner as described in Preparative Example 108above, the morpholino-amine product was obtained.

Preparative Example 110

Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL).N,N′-Dimethylcarbamoyl chloride (1.0 mL, 0.011 mol) was added dropwiseto the solution at room temperature. The reaction was stirred for onehour. After this time 1N potassium hydroxide (200 mL) was added. Thelayers were separated and the aqueous layer was extracted three timeswith dichloromethane. The organic fractions were combined and dried oversodium sulfate. Filtration and concentration provided the product,without further purification, as an oil (1.16 g, 13%).

¹H NMR (CDCl_(3,) 300 MHz) 1.95 (s, 1H), 2.83 (s, 6H), 2.86 (m, 4H),3.20 (m, 4H). MS: calculated: 157.12. found: 158.1.

Preparative Example 111

Piperazine (4.9 g, 0.057 mol) was dissolved in 1N HCl (100 mL). Asolution of phenylsulfonylchloride (1.45 mL, 0.011 mol) in acetonitrile(25 mL) was added dropwise to the solution at room temperature. Thereaction was stirred for 30 minutes. After this time the reaction wasextracted two times with ethyl acetate. The solution was then made basicwith 1N potassium hydroxide and extracted three times withdichloromethane. The dichloromethane fractions were combined and driedover magnesium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (1.22 g, 9.4%).

¹H NMR (CDCl₃, 300 MHz) 2.94 (m, 8H), 7.56 (m, 3H), 7.76 (m, 2H). MS:calculated: 226.08. found: 227.1.

Preparative Example 112

Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL).Methanesulfonyl chloride (0.85 mL, 0.011 mol) was added dropwise to thesolution at room temperature. The reaction was stirred for 30 minutes.After this time 1N potassium hydroxide (200 mL) was added. The layerswere separated and the aqueous layer was extracted three times withdichloromethane. The organic fractions were combined and dried oversodium sulfate. Filtration and concentration provided the product,without further purification, as a solid (1.07 g, 11%).

¹H NMR (CDCl₃, 300 MHz) 1.75 (s, 1H), 2.78 (s, 3H), 2.97 (m, 4H), 3.20(m, 4H). MS: calculated: 164.06. found: 165.1.

Preparative Example 113

Step A

Boc-Piperazine (3.0 g, 0.0161 mol) was dissolved in dichloromethane (100mL). Propylisocyanate (1.51 mL, 0.0161 mol) was added to the solution atroom temperature. The reaction was stirred for over night. After thistime the reaction was diluted with 1N potassium hydroxide (200 mL) andextracted six times with dichloromethane. The organic fractions werecombined and dried over magnesium sulfate. Filtration and concentrationprovided the product as a solid.

Step B

The product of Step A above, was dissolved in a 30% trifluoroaceticacid/dichloromethane solution and stirred overnight. After this time a1N potassium hydroxide solution (200 mL) was added to the reaction. Theaqueous layer was extracted a total of six times with dichloromethane.The organic fractions were combined and dried over sodium sulfate.Filtration and concentration provided the product (1.37 g, 50%).

¹H NMR (CDCl₃, 300 MHz) 0.92 (t, 3H), 1.52 (m, 2H), 2.89 (m, 4H), 3.01(s, 1H), 3.18 (m, 2H), 3.37 (m, 4H), 4.61 (bs, 1H). MS: calculated:171.14. found: 172.0.

Preparative Example 114

Piperazine (4.9 g, 0.0569 mol) was dissolved in 1N HCl (70 mL). Asolution of phenylchloroformate (1.43 mL, 0.0114 mol) in acetonitrile(25 mL) was added dropwise to the solution at room temperature. Thereaction was stirred for 30 minutes. After this time the reaction wasextracted two times with ethyl acetate. The solution was then made basicwith 1N potassium hydroxide and extracted three times withdichloromethane. The dichloromethane fractions were combined and driedover magnesium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (2.12 g, 18%).

¹H NMR (CDCl₃, 300 MHz) 1.78 (s, 1H), 2.91 (m, 4H), 3.59 (m, 4H), 7.11(2H), 7.19 (m, 1H), 7.36 (m, 2H). MS: calculated: 206.24. found: 207.1.

Preparative Example 115–117

Following the procedure described for Example 112, the Products listedin the table below were prepared using the commercially availablechloroformate shown and piperazine.

1. Yield (%) Example Chloroformate Product 2. (M + 1)⁺ 115

1. 54%2. 144.9 116

1. 17%2. 173.0 117

1. 69%2. 173.0

Preparative Example 118

Step A

Boc-Piperazine (3.01 g, 0.0161 mol) was dissolved in dichloromethane(100 mL) along with diisopropylethylamine (5.61 mL, 0.0322 mol).Benzoylchloride (1.87 mL, 0.0161 mol) was added dropwise to the solutionat room temperature. The reaction was stirred for several hours. Afterthis time the reaction was concentrated and the product was purified bycolumn chromatography (10% MeOH/DCM). Boc-Protected product was isolatedas a solid (5.21 g).

¹H NMR (CDCl_(3,) 300 MHz) 1.47 (s, 9H), 3.45 (m, 8H), 7.41 (m, 5H). MS:calculated: 290.16. found: 290.8.

Step B

The product from Step A above, was dissolved in a 50% trifluoroaceticacid/dichloromethane solution and stirred overnight. After this time thereaction was diluted with 1N potassium hydroxide (200 mL) and theorganic layer was separated. The aqueous phase was then extracted sixtimes with dichloromethane. The organic fractions were combined anddried over magnesium sulfate. Filtration and concentration providedproduct (2.93 g).

¹H NMR (CDCl₃, 300 MHz) 1.92 (s, 1H), 2.87 (m, 4H), 3.52 (m, 4H), 7.39(s, 5H). MS: calculated: 190.11. found: 191.1.

Preparative Example 119

Step A

Boc-Piperazine (3.0 g, 0.0161 mol) was dissolved in dichloromethane (100mL) along with diisopropylethylamine (3.1 mL, 0.0177 mol).N,N′-dimethylsulfamoyl chloride (1.73 mL, 0.0161 mol) was added dropwiseto the solution at room temperature. The reaction was stirred forseveral hours. After this time the reaction was diluted with water (100mL). The layers were separated and the aqueous layer was extracted sixtimes with dichloromethane. The organic fractions were combined anddried over magnesium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (4.53 g).

¹H NMR (CDCl_(3,) 300 MHz) 1.47 (s, 9H), 2.84 (s, 6H), 3.21 (m, 4H),3.48 (m, 4H). MS: calculated: 293.14. found: 194.1 (M-Boc)⁺.

Step B

The product from Step A above, was dissolved in a 30% trifluoroaceticacid/dichloromethane solution and stirred overnight. After this time thereaction was diluted with water and 1N potassium hydroxide was used tomake the aqueous layer slightly basic. The aqueous layer was extracted atotal of seven times with dichloromethane. The organic fractions werecombined and dried over sodium sulfate. Filtration and concentrationprovided the product (2.96 g).

¹H NMR (CDCl₃, 300 MHz) 2.03 (s, 1H), 2.83 (s, 6H), 2.92 (m, 4H), 3.23(m, 4H). MS: calculated: 193.09. found: 194.1.

Preparative Example 120

In essentially the same manner as that described in Preparative Example105, Step 1, using 3-nitrobenzoic acid instead of 3-nitrosalicylic acid,the methyl ester product was prepared.

The methyl ester (1.79 g, 6.1 mmol) from Step A above, was dissolved indioxane/water (20 mL/15 mL) at room temperature. Lithium hydroxide(0.258 g, 6.2 mmol) was added to the solution. After a few hours morelithium hydroxide was added (0.128 g, 3.0 mmol) and the reaction wasstirred for another hour. After this time the reaction was concentratedand then taken up in water. The solution was extracted two times withether. The aqueous phase was then acidified and extracted three timeswith ethyl acetate. The organic fractions were then dried over sodiumsulfate, filtered and concentrated. Product was isolated by columnchromatography (95% EtOAc/Hex, 0.05% HOAc) to give the product (1.66 g,98%).

¹H NMR (300 MHz, CDCl₃) 1.49(m, 2H), 1.68(m, 1H), 1.82(m, 2H), 2.44(m,1H) 3.32(m, 1H), 3.58(m, 1H), 5.57(m, 1H), 7.65(m, 1H), 7.80(m, 1H),8.32(m, 2H), 10.04(bs, 1 Hppm).

The nitro compound was dissolved in an excess of methanol (20 mL) andcovered by a blanket of argon. 5% Palladium on carbon was added(catalytic) and a hydrogen balloon was attached to the flask. Theatmosphere of the system was purged under vacuum and replaced withhydrogen. This step was repeated for a total of three times. Thereaction was then stirred under hydrogen overnight. After this time theballoon was removed and the solution was filtered through celitefollowed by several rinses with methanol. The filtrate was concentratedand dried on the vacuum line to provide the desired aniline product(1.33 g. 90%).

¹H NMR (300 MHz, CDCl₃) 1.40(m, 2H), 1.50(m, 1H), 1.68(m, 2H), 2.33(m,1H) 3.18(m, 1H), 3.62(m, 1H), 5.39(m, 1H), 6.12(bs, 2H), 6.75(m, 2H),7.12(m, 1H)ppm. Mass Spectra, calculated: 248. found: 249.1 (M+1)⁺.

Preparative Examples 121–123

Following the procedure described in Preparative Example 120, but usingthe commercially available amine and benzoic acid indicated, theintermediate products in the table below were obtained.

1. Yield (%) Carboxylic 2. (M + 1)⁺ Ex. Acid Amine Product 3. Note 121

1. 21%2. 251.0 122

1. 21%2. 265.03. Skippedstep B 123

1. 15%2. 264.03. Skippedstep B

Preparative Example 124

Step A

3-Nitrosalicylic acid (500 mg, 2.7 mmol), 1,3-dicyclohexylcarbodiimide(DCC) (563 mg) and ethyl acetate (10 mL) were combined and stirred for10 min. (R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and theresulting suspension was stirred at room temperature overnight. Thesolid was filtered off and the filtrate was either concentrated down anddirectly purified or washed with 1N NaOH. The aqueous phase wasacidified and extracted with EtOAc. The resulting organic phase wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the residue by preparative plate chromatography (silicagel, 5% MeOH/CH₂Cl₂ saturated with AcOH) gave the desired compound (338mg, 46%, MH⁺=267).

Step B

The product from Step A above was stirred with 10% Pd/C under a hydrogengas atmosphere overnight. The reaction mixture was filtered throughcelite, the filtrate concentrated in vacuo, and the resulting residuepurified by column chromatography (silica gel, 4% MeOH/CH₂Cl₂ saturatedwith NH₄OH) to give the product (129 mg, 43%, MH+=237).

Preparative Examples 125–145

Following the procedure described for Preparative Example 124, but usingthe commercially available amine or the amine from the PreparativeExample indicated and 3-nitrosalicylic acid, the products in the tablebelow were obtained.

Amine Comm. Avail./ 1. Yield (%) Ex. From Prep. Ex. Product 2. (M + 1)⁺125

1. 37%2. 298.1 126

1. 31%2. 310.1 127

1. 68%2. 294.1 128

1. 54%2. 365.9 129

1. 45%2. 316.1 130 110

1. 59%2. 293.1 131 111

1. 32%2. 362.0 132 114

1. 36%2. 342.0 133 112

1. 65%2. 300.0 134

1. 48%2. 321.1 135

1. 50%2. 300.1 136

1. 56%2. 299.2 137 115

1. 79%2. 280.1 138 116

1. 64%2. 307.1 139

1. 73%2. 304.2 140

1. 34%2. 264.0 141 117

1. 40%2. 307.1 142 113

1. 91%2. 307.1 143 118

1. 9.0%2. 326.0 144 119

1. 42%2. 329.0 145

1. 6.5%2. 236.1

Preparative Example 146

Step A

To a solution of tosylaziridine [J. Am. Chem. Soc. 1998, 120, 6844–6845)(0.5 g, 2.1 mmol) and Cu(acac)₂ (55 mg, 0.21 mmol) in THF (5 mL) at 0°C. was added PhMgBr (3.5 ml, 3.0 M in THF) diluted with THF (8 mL)dropwise over 20 min. The resulting solution was allowed to graduallywarm to rt and was stirred for 12 h. Sat. aq. NH₄Cl (5 mL), was addedand the mixture was extracted with Et₂O (3×15 mL). The organic layerswere combined, washed with brine (1×10 mL), dried (MgSO₄) andconcentrated under reduced pressure. The crude residue was purified bypreparative TLC eluting with hexane/EtOAc (4:1) to afford 0.57 g (86%yield) of a solid. The purified tosylamine was taken on directly to thenext step.

Step B

To a solution of tosylamine (0.55 g, 1.75 mmol) in NH₃ (20 mL) at −78°C. was added sodium (0.40 g, 17.4 mmol). The resulting solution wasstirred at −78° C. for 2 h whereupon the mixture was treated with solidNH₄Cl and allowed to warm to rt. Once the NH₃ had boiled off, themixture was partitioned between water (10 mL) and CH₂Cl₂ (10 mL). Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×10 mL). The organic layers were combined,), dried (NaSO₄), andconcentrated under reduced pressure to a volume of ˜20 mL. 4N HCl indioxane (5 mL) was added and the mixture was stirred for 5 min. Themixture was concentrated under reduced pressure and the resultant cruderesidue was recrystallized from EtOH/Et₂O to afford 0.30 g (87% yield)of a solid.

Preparative Examples 147–156.10

Following the procedure set forth in Preparative Example 146 but usingthe requisite tosylaziridines and Grignard reagents listed in the Tablebelow, the following racemic hydrochloride products were obtained.

Prep Tosyl Grignard Amine Ex. aziridine Reagent hydrochloride 1. Yield(%) 147

MeMgBr

1. 19% 148

EtMgBr

1. 56% 149

n-PrMgBr

1. 70% 150

i-PrMgCl

1. 41% 151

BnMgCl

1. 61% 152

MeMgBr

1. 61% 153

EtMgBr

1. 66% 154

n-PrMgBr

1. 80% 155

i-PrMgBr

1. 27% 156

BnMgCl

1. 79% 156.1

52% 156.2

49% 156.3

61% 156.4

57% 156.5

64% 156.6

64% 156.7

45% 156.8

23% 156.9

40% 156.10

15%

Preparative Example 156.11

Step A

To a solution of the amine (118 mg) from Preparative Example 148 inCH₂Cl₂ (10 ml) was added triethylamine (120 ul), R-Mandelic Acid (164mg), DCC (213 mg) and DMAP (8.8 mg)and let stir for 40 hr. The mixturewas diluted with CH₂Cl₂ and washed with saturated ammonium chloride,dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudematerial was purified by preparative plate chromatography (Hex/EtOAc4:1) to afford both isomers (A, 86 mg, 45%) (B, 90 mg, 48%).

Step B

To isomer B (90 mg) from above in dioxane (5 ml) was added 6M H₂SO₄ (5ml). The reaction was heated to 80° C. over the weekend. 2M NaOH addedto basify the reaction and extracted with ether. Ether layer washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was stirred in 4N HCl in dioxane for 30 min, concentrated invacuo and recrystallized in EtOH/ether to afford 55 mg of product (98%).

Step C

Isomer A (86 mg) was reacted following the procedure set forth in Step Babove to give the amine salt.

Preparative Example 156.12

The above nitro compound was reduced following the Preparative Example2, Step B.

Preparative Example 156.13

To a solution of 1,2-phenylenediame (1.5 g) in CH₂Cl₂ (30 ml) at 0° C.was added TEA (2.91 ml), followed by dropwise addition of MeSO₂Cl (1.07ml). The mixture was allowed to warm to room temperature and stirovernight. 1M HCl added and the layers were separated. The aqueous layerwas adjusted to pH=11 with solid NaOH, extracted with CH₂Cl₂. Thebasified aqueous layer was then neutralized using 3N HCl and extractedwith CH₂Cl₂, dried with Na₂SO₄, filtered, and concentrated in vacuo togive 1.8 g of product (71%).

Preparative Example 156.14

The above compound was prepared using the procedure set forth inPreparative Example 156.13, but using PhSO₂Cl.

Preparative Example 156.15

The nitro compound was reduced following a similar procedure as inPreparative Example 2, Step B.

Preparative Example 156.16

Step A

The known acid (410 mg) above (J. Med. Chem. 1996, 34,4654.) was reactedfollowing the procedure set forth in Preparative Example 2, Step A toyield 380 mg of an oil (80%).

Step B

The amide (200 mg) from above was reacted following the procedure setforth in Preparative Example 2, Step B to yield 170 mg of an oil (100%).

Preparative Example 156.17

Step A

To a solution of ketone (500 mg) in EtOH/water (3:1, 4 ml) at roomtemperature was added hydroxylamine hydrochloride (214 mg) followed byNaOH to afford a heterogenous mixture. The reaction was not complete soanother equivalent of hydroxylamine hydrochloride was added and refluxedovernight. The reaction was cooled to 0° C. and treated with 3N HCl andextracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo to give 500 mg of product (92%).

Step B

To a solution of oxime (300 mg) in THF (5 ml) at 0° C. was added LiAlH₄(266 mg) portionwise. The heterogenous solution was stirred at roomtemperature for 14 hr and then refluxed for 8 hr. The solution wascooled to 0° C. and water, 2M NaOH, water and ether were added to thereaction. The mixture was filtered through a celite pad. The filtratewas treated with 3N HCl. The aqueous layer was cooled to 0° C., basifiedwith NaOH pellets and extracted with ether. The ether layer was driedover MgSO₄, filtered, and concentrated in vacuo to afford the product(143 mg, 69%).

Preparative Example 156.18

Step A

Methoxyacetic acid (14 mL) in CH₂Cl₂ (120 mL) and cooled in an ice-waterbath was treated with DMF (0.9 mL) and oxalyl chloride (21 mL). Afterstirring at RT overnight, the mixture was concentrated in vacuo andredissolved in CH₂Cl₂ (120 mL). N-methyl-N-methoxylamine (20 g) wasadded and the mixture stirred at RT overnight. Filtration andconcentration in vacuo afforded the desired amide (21 g, 89%).

Step B

To a solution of the above amide (260 mg) in THF (5 ml) at −78° C. wasadded a solution of 2-thienyllithium (1M in THF, 2.15 ml). The solutionwas stirred for 2 hr at −78° C. and warmed to −20° C. for an additional2 hr. The reaction was quenched with saturated ammonium chloride andextracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo to give 250 mg of product (82%).

Step C

The ketone from above (250 mg) was reacted via the procedure set forthin Preparative Example 156.17 Steps A and B to yield 176 mg of the amine(79%).

Preparative Example 156.19

Step A

To a solution of 3-chlorothiophene (1.16 ml) in ether (20 ml) at −10° C.was added n-BuLi (2.5M in hexane, 5 ml). After solution was stirred at−10° C. for 20 min, propionaldehyde (0.82 ml) in ether (20 ml) was addeddropwise and let warm to room temperature slowly. The reaction wasquenched with saturated ammonium chloride and extracted with CH₂Cl₂,washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo to give 1.37 g of product (62%).

Step B

The alcohol from Step A above was reacted via the procedures set forthin Preparative Example 75.75, Steps B and C to give the amine.

Preparative Example 156.20

Step A

To a solution of magnesium metal (360 mg) in THF (15 ml) at 0° C. wasadded 2-bromothiophene (1.45 ml) in THF (10 ml) dropwise over 20 min.The solution was warmed to room temperature for 3 hr, recooled to 0° C.whereupon a solution of cyclopropylacetonitrile (1 g) in ether (30 ml)was added dropwise via a syringe and let warm to room temperature andstir overnight. 3M HCl was added and washed with CH₂Cl₂. The aqueouslayer was basified with NaOH pellets and extracted with ether, driedwith Na₂SO₄, filtered, and concentrated in vacuo to give 625 mg ofproduct (68%).

Step B

The ketone was reacted via the procedure set forth in PreparativeExample 156.17 Step A to give the oxime.

Step C

The oxime from above was reacted via the procedure set forth inPreparative Example 156.17 Step B to give the amine.

Preparative Example 156.21

Step A

To a solution of CH₃ONHCH₃.HCl (780 mg) and acid chloride (1 g) inCH₂Cl₂ at 0° C. was added dry pyridine (1.35 ml) to afford aheterogenous mixture The solution was warmed to room temperature andstirred overnight. 1 M HCl was added to the reaction and the organiclayer was separated, washed with brine, dried with Na₂SO₄, filtered, andconcentrated in vacuo to give 1 g of product (85%).

Step B

To a solution of Etl (614 ul) in ether (5 ml) at −78° C. was addedt-BuLi (1.7M in pentane, 9 ml) dropwise. The mixture was warmed to roomtemperature for 1 hr, cooled to −78° C. where the amide (1 g) from StepA in THF (4 ml) was added and allowed to warm to 0° C. for 2 hr. 1M HClwas added to the reaction and extracted with CH₂Cl₂, washed with brine,dried with Na₂SO₄, filtered, and concentrated in vacuo to give 500 mg ofproduct (63%).

Step C

To a solution of ketone (800 mg) in THF/water (10:1, 20 ml) at 0° C. wasadded sodium borohydride (363 mg) portionwise. The solution was stirredfor 2 hr at 0° C. The mixture was concentrated in vacuo, the residue wasdissolved in CH₂Cl₂, washed with 1N NaOH and brine, dried with Na₂SO₄,filtered, and concentrated in vacuo to give 560 mg of product (69%).

Step D

The alcohol from above was reacted via the procedures set forth inPreparative Example 75.75, Steps B and C to give the amine (176 mg,59%).

Preparative Example 156.22

Step A

Cyclopropylacetonitrile (12 mmol) in Et₂O (50 mL) at 0° C. was treatedwith PhMgBr (14 mmol) and the mixture was stirred for 2 hrs at 0° C.,then at RT overnight. Hydrochloric acid (3M) was added, and afterstirring for an additional 12 hrs, the mixture was extracted withCH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered and concentratedin vacuo to give the desired ketone (1.34 g, 70%).

Step B

Following the procedures set forth in Preparative Example 156.20 Steps Band C, the amine was prepared.

Preparative Example 156.23

The above amine was prepared using the procedures set forth in WO PatentPublication 98/11064.

Preparative Example 157

Step A

By taking the known carboxylic acid [J. Med. Chem. 1996, 39, 4654–4666]and subjecting it to the conditions outlined in Preparative Example 112,the product can be prepared.

Step B

Following a similar procedure used in Preparative Example 2, Step A,except using dimethylamine and the compound from Step A above, theproduct can be prepared.

Step C

Following a similar procedure used in Preparative Example 2, Step B,except using the compound from Step B above, the product can beprepared.

Preparative Example 158

Following a similar procedure used in Preparative Example 157, StepsA–C, except using trifluoromethylsulfonylchloride in Step A above, theproduct can be prepared.

Preparative Example 500.1

Step A

By using the nitro-amide from Preparative Example 13.3, Step A, theamidine structure can be prepared following a similar procedure to thatin Tetrahedron Lett., 2000, 41 (11), 1677–1680.

Step B

By using the product from Step A and the procedure set forth inPreparative Example 2, Step B, one could obtain the desiredamine-amidine.

Alternate Preparative Example 500.2

Step A

By treating the nitro-amide from Preparative Example 13.3, Step B withPOCl₃ and subsequently MeNH₂, according to procedures known in the art,one would obtain the desired compound.

Step B

By treating the product from Step A according to the procedure set forthin Preparative Example 13.3, Step E, one could obtain the desiredcompound.

Step C

By using the product from Step B and the procedure set forth inPreparative Example 2 Step B, one would obtain the desired compound.

Preparative Example 500.3

Step A

By following a similar procedure as that described in Zh. Obshch. Khim.,27, 1957, 754, 757., but instead using 2,4-dichlorophenol anddimethylphosphinic chloride, one would obtain the desired compound.

Step B

By following a similar procedure as that described in J. Organomet.Chem.; 317, 1986, 11–22, one would obtain the desired compound.

Step C

By following a similar procedure as that described in J. Amer. Chem.Soc., 77, 1955, 6221, one would obtain the desired compound.

Step D

By following a similar procedure as that described in J. Med. Chem., 27,1984, 654–659, one would obtain the desired compound.

Alternate Preparative Example 500.4

Step A

By following a similar procedure as that described in Phosphorous,Sulfur Silicon Relat. Elem.; EN; 61, 12, 1991, 119–129, but insteadusing 4-chlorophenol, one would obtain the desired compound.

Step B

By using a similar procedure as that in Phosphorous, Sulfur SiliconRelat. Elem.; EN; 61, 12, 1991, 119–129, but instead using MeMgBr, thedesired compound could be prepared.

Step C

By following a similar procedure as that described in J. Amer. Chem.Soc., 77, 1955, 6221, one would obtain the desired compound.

Step D

By following a similar procedure as that described in J. Med. Chem., 27,1984, 654–659, one would obtain the desired compound.

Preparative Example 500.5

By following a similar procedure as that set forth in J. Org. Chem.1998, 63, 2824–2828, but using CH₃CCMgBr, one could obtain the desiredcompound.

Preparative Example 500.6

Step A

By following the procedure set forth in Preparative Example 13.1, Step Busing 3-methoxythiophene, one can obtain the desired product.

Step B

By using the product from step A and following the procedure set forthin Preparative Example 13.19, Step E, the desired compound can beobtained.

Step C

By using the product from Step B and following the procedure set forthin Preparative Example 13.29, Step D, one can obtain the desiredcompound.

Step D

By using the product from Step C and following the procedure set forthin Preparative Example 13.3, Step B, the desired compound can beobtained.

Step E

By treating the product from Step D with n-BuLi at −78° C. in THF andquenching the resulting anion with CO₂ according to standard literatureprocedure, one would obtain the desired compound following aqueous acidwork up.

Step F

By using the product from Step E and the procedure set forth inPrepartive Example 13.19, Step C, one could obtain the desired compound.

Step G

By using the product from step F and following the procedure set forthin Preparative Example 13.19, Step E, the desired compound can beobtained.

Step H

By using the product from Step G and following the procedure set forthin Preparative Example 2, Step B, the desired compound can be obtained.

Step I

By using the product from Step H and following the procedure set forthin Preparative Example 19, the desired compound can be prepared.

Example 200

To a solution of the HCl salt product (83 mg, 0.50 mmol) fromPreparative Example 24, in EtOH (3 mL) at room temperature was addedEt₃N (55 μL, 0.50 mmol) and the mixture was stirred for 10 min. Thecyclobutenedione (100 mg, 0.33 mmol) from Preparative Example 19 in EtOHwas then added in a single portion and the mixture was stirred for 12 hat room temperature. The mixture was concentrated under reduced pressureand was purified by preparative TLC (4×1000 μM plates) eluting withCH₂Cl₂/MeOH (25:1) to afford 116 mg (91% yield) of the desired productas a solid [MH+389.1, mp 241–243° C.].

Examples 201–209

Following the procedure set forth in Preparative Example 200 but usingthe appropriate amine hydrochlorides from Preparative Examples 25–33 asidentified and the cyclobutenedione intermediate from PreparativeExample 19, the cyclobutenedione products in the Table below wereobtained.

1. Yield (%) (Prep Ex.) 2. MH⁺ Ex. Amine Product 3. mp (° C.) 201 (25)

1. 89%2. 375.13. 255.5–257.3 202 (26)

1. 92%2. 465.13. 149.0–152.3 203 (27)

1. 68%2. 451.13. 282–284 204 (28)

1. 74%2. 493.13. 141 205 (29)

1. 48%2. 479.13. 142 206 (30)

1. 41%2. 479.13. 142 207 (31)

1. 59%2. 479.13. 141 208 (32)

1. 34%2. 493.13. 140 209 (33)

1. 40%2. 493.13. 142 209.1 (33.1)

1. 59%2. 143–145

Example 209.2

The crude amine product from Preparative Example 33.2 and thecyclobutendione component from Preparative Example 19.1(36 mg) weredissolved in MeOH/DIEA (2.5 ml/5/1) and irradiated via microwave (50W,1hr). The reaction was concentrated in vacuo and purified by Gilsonsemi-prep. HPLC to give the final product (68%, MH+=485.2).

Examples 209.3–209.50

Following the procedure set forth in Example 209.2, but using theprepared amine from the Preparative Example indicated in the Tablebelow, the following cyclobutenedione products were obtained.

(Prep Ex.) 1. Yield (%) Ex. Amine Product 2. MH⁺ 209.3 (33.3)

1. 50%2. 541.2 209.4 (33.4)

1. 32%2. 549.1 209.5 (33.5)

1. 65%2. 493.1 209.6 (33.6)

1. 64%2. 491.1 209.10 (33.7)

1. 90%2. 457.2 209.11 (33.8)

1. 35%2. 505.0 209.12 (33.9)

1. 70%2. 493.1 209.13 (33.10)

1. 75%2. 480.2 209.14 (33.11)

1. 74%2. 465.1 209.15 (33.12)

1. 62%2. 479.1 209.16 (33.13)

1. 31%2. 466.2 209.17 (33.14)

1. 79%2. 495.2 209.18 (33.15)

1. 99%2. 479.2 209.19 (33.16)

1. 47%2. 466.2 209.20 (33.17)

1. 72%2. 479.1 209.21 (33.18)

1. 92%2. 493.1 209.22 (33.19)

1. 47%2. 499.1 209.23 (33.20)

1. 7%2. 490.0 209.24 (33.21)

1. 15%2. 533.1 209.25 (33.22)

1. 88%2. 451.1 209.26 (33.23)

1. 26%2. 523.0 209.27 (33.24)

1. 54%2. 433.1 209.28 (33.25)

1. 59%2. 466.2 209.29 (33.26)

1. 66%2. 560.2 209.30 (33.27)

1. 98%2. 495.1 209.31 (33.28)

1. 99%2. 471.2 209.32 (33.29)

1. 99%2. 471.2 209.33 (33.30)

1. 18%2. 524.2 209.34 (33.31)

1. 78%2. 479.2 209.35 (33.32)

1. 71%2. 459.2 209.36 (33.33)

1. 5%2. 491.0 209.37 (33.34)

1. 27%2. 501.1 209.38 (33.35)

1. 26%2. 533.1 209.39 (33.36)

1. 48%2. 451.1 209.40 (33.37)

1. 99%2. 455.1 209.41 (33.38)

1. 88%2. 527.1 209.42 (33.39)

1. 74%2. 485.2 209.43 (33.40)

1. 20%2. 492.5 209.44 (33.41)

1. 68%2. 541.1 209.45 (33.42)

1. 13%2. 508.9 209.46 (33.43)

1. 86%2. 479.1 209.47 (33.44)

1. 34%2. 507.0 209.48 (33.45)

1. 56%2. 429.1 209.49 (33.46)

1. 18%2. 495.0 209.50 (33.47)

1. 22%2. 501.0

Example 210

To a solution of amine (0.17 g, 1 mmol) from Preparative Example 34 inEtOH (3 mL) at room temperature was added the cyclobutenedione fromPreparative Example 19 (100 mg, 0.33 mmol) in one portion. The resultingmixture was stirred for 5 h (until TLC analysis revealed reactioncomplete) and was concentrated under reduced pressure. The crude residuewas redissolved in CH₂Cl₂ (15 mL) and was washed sequentially with 10%KH₂PO₄ (2×15 mL) and brine (1×15 mL). The organic layer was dried(Na₂SO₄) and concentrated under reduced pressure to afford the crudeadduct. The crude product was purified by prep TLC (4×1000 uM plates)eluting with CH₂Cl₂/MeOH (20:1) to afford 83 mg (59% yield) of thedesired product as a solid.

Examples 211–260

Following the procedure set forth in Example 210 but using thecommercially available amine or the prepared amine from the PreparativeExample indicated in the Table below, the following cyclobutenedioneproducts were obtained.

1. Yield (%) (Prep Ex) 2. MH⁺ Ex. Amine Product 3. mp (° C.) 211

1. 75%2. 412.13. 126 212

1. 42%2. 438.13. 106 213

1. 73%2. 428.13. 139 214

1. 40%2. 462.13. 160 215

1. 52%2. 408.13. 126 216

1. 32%2. 478.13. 176 217

1. 50%2. 412.13. 126 218

1. 55%2. 478.13. 100 219

1. 67%2. 438.13. 122 220

1. 73%2. 462.13. 118 221

1. 67%2. 424.13. 100 222

1. 61%2. 478.13. 114 223

1. 50%2. 408.13. 157–159 224

1. 75%2. 366.13. 110–112 225

1. 81%2. 380.13. 118–120 226

1. 69%2. 394.13. 123–125 227

1. 80%2. 367.13. 122–125 228

1. 72%2. 381.13. 133–135 229

1. 81%2. 395.13. 141–145 230

1. 75%2. 356.13. 103–104 231

1. 24%2. 370.13. 101 232

1. 16%2. 384.13. 70 233

1. 72%2. 373.43. 104–106 234

1. 34%2. 387.13. 99 235

1. 48%2. 380.13. 118–120 236

1. 72%2. 380.13. 119–120 237

1. 72%2. 398.13. 121–123 238

1. 44%2. 398.13. 121–123 239

1. 60%2. 394.13. 123–124 240

1. 52%2. 394.13. 122–124 241

1. 34%2. 428.43. 157–159 242

1. 70%2. 412.13. 109–112 243

1. 69%2. 412.13. 110–112 244

1. 89%2. 412.13. 126 245

1. 81%2. 412.13. 126 246

1. 65%2. 424.13. 121–124 247

1. 73%2. 424.13. 122–124 248

1. 29%2. 372.13. 219–221 249

1. 66%2. 394.13. 132–135 250

1. 72%2. 332 251

1. 74%2. 408.13. 121–123 252

1. 76%2. 408.13. 102–104 253

1. 72%2. 438.13. 75–77 254

1. 80%2. 392.13. 98–101 255

1. 72%2. 420.13. 200–205 256

1. 75%2. 434.13. 138–140 257

1. 67%2. 410.13. 116–118 258

1. 76%2. 424.13. 108–110 259

1. 72%2. 430.13. 125 260

1. 78%2. 422.13. 127 260.1

1. 74%2. 426.13. 114 DEC 260.2

1. 85%2. 436.13. 143 DEC 260.3

1. 56%2. 474.13. 121–123 260.4

1. 71%2. 500.13. 97 (DEC) 260.6

1. 61%2. 4653. 102–107 260.7

1. 78%2. 422.13. 114 DEC 260.8

1. 35%2. 486.13. 103–105 260.9

1. 79%2. 4703. 110–115 260.10

1. 62%2. 462.13. 110 DEC 260.11

1. 61%2. 446.13. 118 DEC 260.12

1. 58%2. 480.13. 111 DEC 260.13

1. 87%2. 438.13. 122 260.14

1. 74%2. 408.13. 128–130 260.15

1. 78%2. 430.13. 117 DEC 260.16

1. 81%2. 452.13. 139 260.17

1. 85%2. 426.13. 126 260.18

1. 50%2. 482.13. 114–116 260.19

1. 64%2. 450.13. 129 260.20

1. 72%2. 424.13. 116 260.21

1. 35%2. 434.13. 124 260.22

1. 58%2. 420.13. 107–109 260.23

1. 69%2. 440.13. 169 260.24

1. 15%2. 404.13. 103–105 260.25

1. 92%2. 434.13. 129 260.26

1. 77%2. 434.13. 133 260.27

1. 73%2. 434.13. 138 260.28

1. 37%2. 434.13. 133

Example 261

To a solution of the amine (77 μL, 0.66 mmol) in EtOH (3 mL) at roomtemperature was added the product from Preparative Example 19 (100 mg,0.33 mmol) in one portion. The resulting mixture was stirred for 5 h(until TLC analysis revealed reaction complete) and was thenconcentrated under reduced pressure. The crude residue was redissolvedin CH₂Cl₂ (15 mL) and was washed sequentially with 10% KH₂PO₄ (2×15 mL)and brine (1×15 mL). The organic layer was dried (Na₂SO₄) andconcentrated under reduced pressure to afford the crude adduct. Thecrude product was purified by prep TLC (4×1000 uM plates) eluting withCH₂Cl₂/MeOH (20:1) to afford 82 mg (72% yield) of the desired product asa solid. (mp 126.0–128.0° C., MH⁺346)

Examples 262–360.117

Following the procedure set forth in Example 261 but using thecommercially available amine or the prepared amine from the PreparativeExample indicated in the table below, the following cyclobutenedioneproducts were obtained.

1. Yield (%) 2. MH⁺ Ex. Amine Product 3. mp (° C.) 262

1. 74%2. 330.13. 112–115 263

1. 64%2. 344.13. 120–122 264

1. 72%2. 358.43. 129–132 265

1.76%2. 372.13. 141–143 266

1. 57%2. 372.13. 102 267

1. 65%2. 386.13. 146 268

1. 65%2. 464.13. 110–112 269

1. 85%2. 464.13. 111–113 270

1. 49%2. 374.13. 146 271

1. 69%2. 374.13. 158–162 272

1. 54%2. 430.13. 108 273

1. 65%2. 430.13. 110 274

1. 53%2. 388.13. 136 275

1. 30%2. 388.13. 114 276

1. 53%2. 402.13. 126 277

1. 68%2. 402.13. 116 278

1. 64%2. 372.13. 106 279

1. 69%2. 434.13. 141–143 280

1. 51%2. 434.13. 148–150 281

1. 71%2. 406.13. 146–148 282

1. 66%2. 406.13. 141–144 283

1. 70%2. 450.13. 97–99 284

1. 25%2. 360.13. 139 285

1. 78%2. 416.13. 94 286

1. 49%2. 372.13. 139 287

1. 95%2. 386.13. 139 288

1. 32%2. 3483. 130–133 289

1. 72%2. 410.13. 138 290

1. 72%2. 410.13. 132–134 291

1. 75%2. 318.13. 96–98 292

1. 72%2. 430.13. 125 293

1. 51%2. 3483. 109–111 294

1. 84%2. 3743. 150.3 295

1. 56%2. 3863. 142.3 296

1. 38%2. 3823. 173.4 297

1. 13%2. 3703. 135.1 298

1. 47%2. 4243. 231.2–234.5 299

1. 34%2. 3163. 209.5 300

1. 92%2. 3923. 152.7 301

1. 52%2. 3463. 124.7 302

1. 51%2. 3463. 139.2 303

1. 29%2. 4083. 105 304

1. 24%2. 3723. 223.2 305

1. 25%2. 4423. 219.0 306

1. 83%2. 3863. 145 307

1. 58%2. 4003. 99.6 308

1. 60%2. 4143. 123.6 309

1. 44%2. 4123. 146.7 310

1. 39%2. 4323. 156.6 311

1. 65%2. 4483. 162.8 312

1. 53%2. 4493. 139.7 313

1. 64%2. 4543. 143.2 314

1. 35%2. 4283. 146.8 315

1. 72%2. 4763. 139.4 316

1. 36%2. 4023. 89.6 317

1. 62%2. 4003. 130.2 318

1. 46%2. 4003. 123.6 319

1. 64%2. 4003. 132.5 320

1. 79%2. 4063. 123.3 321

1. 17%2. 4403. 157.6 322

1. 58%2. 4283. 167.9 323

1. 50%2. 4223. 150.2 324

1. 20%2. 4623. 113.9 325

1. 95%2. 3603. 129.2 326

1. 97%2. 3603. 131.5 327

1. 39%2. 3183. 138.5 328

1. 54%2. 4083. 152.3 329

1. 62%2. 3463. 134.8 330

1. 55%2. 3463. 145.1 331

1. 61%2. 4003. 137.6 332

1. 42%2. 3743. 155.1 333

1. 45%2. 3483. 108–110 334

1. 29%2. 4243. 116 335

1. 15%2. 4143. 108–110 336

1. 75%2. 4083. 116 337

1. 75%2. 4083. 116 338

1. 59%2. 4243. 115–117 339

1. 72%2. 4243. 157–159 340

1. 19%2. 3323. 131 341

1. 86%2. 3603. 127 342

1. 98%2. 3463. 128 343

1. 80%2. 3743. 131.5 344

1. 46%2. 3743. 102 345

1. 75%2. 3883. 104 346

1. 76%2. 4383. 95 347

1. 72%2. 4243. 163–165 348

1. 73%2. 4383. 96–98 349

1. 53%2. 3623. 89–91 350

1. 59%2. 3623. 90–92 351

1. 61%2. 3623. 120–122 352

1. 70%2. 3623. 121–123 353

1. 23%2. 3713. 126 354

1. 79%2. 3703. 108 355

1. 80%2. 3703. 106 356

1. 56%2. 4503. 138–140 357

1. 76%2. 3983. 116 358

1. 85%2. 3843. 100 359

1. 59%2. 3323. 138.6 360

1. 47%2. 3323. 141.6 360.1

1. 89%2. 356.13. 133–135 360.2

1. 65%2. 334.13. 121–122 360.3

1. 60%2. 348.13. 94–96 360.4

1. 29%2. 414.13. 108–110 360.5

1. 67%2. 348.13. 95–96 360.6

1. 62%2. 414.13. 113–115 360.7

1. 68%2. 414.13. 114–116 360.8

1. 74%2. 3743. 129.8 360.9

1. 61%2. 3883. 123.1 360.10

1. 53%2. 3883. 117.2 360.11

1. 37%2. 3883. 129.9 360.12

1. 62%2. 3743. 126.1 360.13

1. 71%2. 400.13. 106–109 360.14

1. 66%2. 400.13. 106–109 360.15

1. 69%2. 3723. 138.7 360.16

1. 54%2. 3463. 123.6 360.17

1. 53%2. 3883. 116.9 360.18

1. 87%2. 384.13. 136 360.19

1. 92%2. 384.13. 136 360.20

1. 27%2. 386.13. 109–112 360.21

1. 31%2. 400.13. 117–120 360.22

1. 61%2. 396.13. 129 360.23

1. 69%2. 396.13. 126 360.24

1. 74%2. 398.13. 123 360.25

1. 76%2. 398.13. 123 360.26

1. 60%2. 384.13. 103–105 360.27

1. 67%2. 384.13. 104‥106 360.28

1. 70%2. 386.13. 103–105 360.29

1. 64%2. 400.13. 109–111 360.30

1. 63%2. 398.13. 99–101 360.31

1. 57%2. 398.13. 99–101 360.32

1. 45%2. 4003. 104.6 360.33

1. 44%2. 3863. 143 360.34

1. 73%2. 356.13. 218–220 360.35

1. 97%2. 406.13. 154 360.36

1. 77%2. 414.13. 122–124 360.37

1. 70%2. 412.13. 99–101 360.38

1. 69%2. 416.13. 107–109 360.39

1. 43%2. 454.13. 128–130 360.40

1. 40%2. 374.13. 132–136 360.41

1. 60%2. 345.13. 205–207 360.42

1. 96%2. 412.13. 112 360.43

1. 30%2. 434.13. 117–119 360.44

1. 96%2. 410.13. 139 360.45

1. 65%2. 384.13. 87–89 360.46

1. 50%2. 434.13. 123–125 360.47

1. 74%2. 412.13. 84–86 360.48

1. 73%2. 400.13. 136–140 360.49

1. 74%2. 412.13. 103–105 360.50

1. 63%2. 434.13. 114–117 360.51

1. 74%2. 414.13. 130–133 360.52

1. 71%2. 426.13. 138 360.53

1. 41%2. 4143. 139–141 360.54

1. 32%2. 4263. 148–150 360.55

1. 57%2. 4283. 159–163 360.56

1. 44%2. 464.13. 86–88 360.57

1. 37%2. 4423. 158–162 360.58

1. 53%2. 494.13. 148–151 360.59

1. 63%2. 528.13. 90–95 360.60

1. 73%2. 438.13. 116 360.61

1. 55%2. 494.13. 133–135 360.62

1. 83%2. 412.13. 119 360.63

1. 66%2. 440.13. 110 360.64

1. 49%2. 410.13. 97 360.65

1. 40%2. 442.13. 157–160 360.66

1. 75%2. 4003. 136–140 360.67

1. 63%2. 528.13. 106–108 360.68

1. 10%2. 401.13. 111–113 360.69

1. 5%2. 426.1 360.70

1. 56%2. 442.13. 152–154 360.71

1. 46%2. 414.13. 122–124 360.72

1. 62%2. 385.13. 130–133 360.73

1. 41%2. 399.13. 83–85 360.74

1. 70%2. 414.13. 98–101 360.75

1. 62%2. 441.13. 98–102 360.76

1. 79%2. 464.13. 111 360.77

1. 79%2. 418.13. 107 360.78

1. 65%2. 400.13. 109–112 360.79

1. 21%2. 428.13. 126 360.80

1. 55%2. 493.13. 155–158 360.81

1. 67%2. 428.13. 138–140 360.82

1. 68%2. 426.13. 121–123 360.83

1. 25%2. 427.13. 139 360.84

1. 62%2. 413.13. 128 360.85

1. 49%2. 460.13. 112–114 360.86

1. 71%2. 434.13. 91–93 360.87

1. 57%2. 411.13. 125 360.88

1. 12%2. 400.13. 131–133 360.89

1. 60%2. 464.13. 111–113 360.90

1. 60%2. 418.13. 113 360.91

1. 55%2. 415.13. 140–143 360.92

1. 55%2. 4293. 185–190 360.93

1. 3%2. 447.1 360.94

1. 71%2. 452.13. 106 360.95

1. 44%2. 439.13. 112 360.96

1. 71%2. 464.13. 111–113 360.97

1. 70%2. 398.13. 106–108 360.98

1. 46%2. 426.13. 140–142 360.99

1. 62%2. 399.13. 109–112 360.100

1. 60%2. 466.13. 129–131 360.101

1. 49%2. 446.13. 146 360.102

1. 48%2. 432.13. 116 360.103

1. 62%2. 418.13. 126 360.104

1. 47%2. 430.13. 136 360.105

1. 42%2. 461.13. 131–134 360.106

1. 93%2. 426.13. 123–125 360.107

1. 26%2. 454.13. 132–134 360.108

1. 12%2. 479.13. 129–132 360.109

1. 67%2. 410.13. 119–121 360.110

1. 71%2. 4123. 102 360.111

1. 64%2. 440.13. 91–93 360.112

1. 79%2. 4123. 111–113 360.113

1. 20%2. 440.13. 130(DEC) 360.114

1. 61%2. 438.13. 117–119 360.115

1. 61%2. 440.13. 117–119 360.116

1. 81%2. 4523. 118 360.117

1. 65%2. 4663. 109

Examples 361–368.45

Following the procedure set forth in Example 261 but using thecommercially available amine in the table below and the cyclobutenedioneintermediate from the Preparative Example indicated, the followingcyclobutenedione products were obtained.

1. Yield (%) Prep. 2. MH⁺ Ex. Amine Ex. Product 3. mp (° C.) 361

20

1. 57%2. 4223. 172.4 362

21

1. 53%2. 4083. 139.8 363

21

1. 70%2. 3743. 167.8–170.1 364

23

1. 21%2. 3343. 184.3 365

23

1. 61%2. 3483. 205.6 366

21.1

1. 75%2. 3443. 170–172 367

21.1

1. 66%2. 3303. 160–162 368

22

1. 31%2. 4363. 140–145 368.1

20

1.  8%2. 3743. 130–133 368.2

23.1

1. 56%2. 3723. 188–191 368.3

23.1

1. 67%2. 4063. 142–144 368.4

23.2

1. 69%2. 4083. 147–150 368.5

23.2

1. 67%2. 3743. 177–180 368.6

23.3

1. 45%2. 3853. 236–240 368.7

23.3

1. 35%2. 4253. 248–251 368.8

23.2

1. 66%2. 4143. 156–160 368.9

23.4

1. 78%2. 4283. 138–140 368.10

23.5

1. 46%2. 4283. 149–153 368.11

23.6

1. 54%2. 4123. 136–138 368.12

21

1. 30%2. 4143. 164–167 368.13

23.1

1. 25%2. 4123. 172–177 368.14

23.7

1. 21%2. 4343. 208–211 368.15

23.8

1. 27%2. 4783. 216–219 368.16

23.9

1. 63%2. 400 368.17

23.9

1. 61%2. 406.13. 127 DEC 368.18

23.9

1. 68%2. 436.13. 128 DEC 368.19

23.9

1. 72%2. 404.13. 126 DEC 368.20

23.10

1.  8.4%2. 478 368.21

23.9

1. 39%2. 432.13. 151–153 368.22

23.12

1. 78%2. 414.13. 210 DEC 368.23

23.11

1.  4%2. 504 368.24

23.11

1. 31%2. 4903. 241–245 368.25

23.9

1. 81%2. 420.13. 126–128 368.26

23.11

1.  8%2. 4763. 193–198 368.27

23.9

1. 70%2. 434.13. 130 DEC 368.28

23.11

1. 83%2. 5063. 222–227 368.29

23.11

1. 17%2. 4643. 183–190 368.30

23.13

1.  6.5%2. 438.1 368.31

23.14

1. 71%2. 471.13. 149–151 368.32

23.14

1. 58%2. 471.13. 149 368.33

23.15A

1. 33%2. 440.13. 181 368.34

23.15A

1. 56%2. 4683. 180 368.35

23.15A

1. 28%2. 4803. 186 368.36

23.15A

1. 48%2. 4943. 112.5 368.37

23.15B

1. 58%2. 5923. 177–179 368.38

23.15C

1. 69%2. 5163.  88–90 368.39

23.15D

1. 80%2. 5303. 134–137 368.40

23.15E

1. 57%2. 4543. 138–140 368.41

19.2

1. 26%2. 5073. 162–164 368.42 3 23.25

1. 82%2. 4663. 141–143 368.43 3 23.26

1. 67%2. 4803. 139 dec 368.44 13.29 23.16

1. 29%2. 4803. 112–114 368.45 13.29 23.26

1. 88%2. 5083. 190 dec

Examples 369–378.23

Following the procedure set forth in Example 210 but using thecyclobutenedione intermediate from Preparative Example indicated and theamine from the Preparative Example indicated in the Table below, thefollowing cyclobutenedione products were obtained.

Prep Ex of Cyclo- butene 1. Yield (%) Prep Ex of Inter- 2. MH⁺ Ex. Aminemediate Product 3. mp (° C.) 369 8 87

1. 41%2. 4223. 135–140 370 9 87

1. 60%2. 4203. 120–125 371 10 87

1. 59%2. 4503. 162–167 372 12 87

1. 34%2. 4193. 157.2–168.2 373 12 88

1. 18%2. 3713. 1.42.3–144.6 374 13 87

1. 41%2. 4083. 245.3–247.8 375 5 87

1. 32%2. 3663. 165.7 376 6 87

1. 17%2. 3803. 173.5 377 7 87

1.48%2. 4363. 175.6 378

87

1.62%2. 3643. 155–160 378.1 3 88.3

1. 73%2. 438.13. 116 378.2 3 88.2

1. 58%2. 4543. 140–142 378.3 13.3 87

1. 43%2. 472206–209 378.4 3 23.16

1. 69%438.13. 116 378.5 3 23.17

1. 73%2. 438.13. 116 378.6 13.4 87

1. 10%2. 4703. 198–201 DEC 378.7 13.5 87

1. 16%2. 4713. 246–248 378.8 13.3 23.16

1. 30%2. 516/5183. 234–240 DEC 378.9 13.19 23.16

1. 65%2. 444.1 378.10 3 23.20

1. 78%2. 4883. 137–140 378.11

88.1

1. 24%2. 3713. 254–260 DEC 378.12 13.6 88.1

1.  3%2. 542 378.13 13.7 88.1

1.  9%2. 542 378.14

88.1

1. 48%2. 4343. 150–152 378.15 3 23.19

1. 71%2. 4883. 136–138 378.16 3 23.22

1. 35%2. 424.13. 132 378.17 13.9 88.1

1. 13%2. 4403. 219–223 378.18 13.10 88.1

1. 25%2. 4063. 242–249 DEC 378.19 13.8 88.1

1. 18%2. 395 378.20 3 23.18

1. 53%2. 478.13. 126 378.21 3 23.21

1. 66%2. 4663. 106 378.22 3 23.24

1. 73%2. 502.13. 121 378.23 3 23.23

1. 57%2. 458.13. 129

Examples 378.25–378.89

Following the procedure set forth in Example 210 but using thecyclobutenedione intermediate from Preparative Example indicated and theamine from the Preparative Example indicated in the Table below, thefollowing cyclobutenedione products were obtained.

Prep Ex of Cy- clo- bu- tene Inter- 1. Yield Prep Ex medi- (%) Ex. ofAmine ate Product 2. MH⁺ 378.25 11.10 87.1

1. 71%2. 480.0 378.26 10.28 87.1

1. 60%2. 449.9 378.27 11.11 88.4

1. 25%2. 540.1[M +Na⁺] 378.28 10.36 87.1

1. 16%2. 465.0 378.29 10.7 88.5

1. 46%2. 440.4 378.30 10.9 88.4

1. 43%2. 934.9[dimer +1]³⁰ 378.31 11.12 88.4

1. 48%2. 464.0 378.32 10.35 87.1

1. 17%2. 437 378.33 10.8 87.1

1. 10%2. 481.9 378.34 11.13 87.1

1. 55%2. 463.9 378.35 10.29 87.1

1. 34%2. 471.9 378.36 10.48 87.1

1.  4%2. 433.9 378.36A 10.10 87.1

1. 85%2. 451.9 378.37 10.31 87.1

1. 36%2. 423.8 378.38 10.17 87.1

1. 85%2. 521.1 378.39 10.32 87.1

1. 63%2. 409.9 378.40

87.1

1. 44%2. 323.1 378.41 10.33 87.1

1. 20%2. 486.0 378.42 10.13 87.1

1. 47%2. 520.1 378.43 10.34 87.1

1. 18%2. 449.9 378.44 11.14 87.1

1. 13%2. 424.0 378.45 2.13 87.1

1. 13%2. 423.8 378.46 12.1 87.1

1. 51%2. 487.1 378.47 10.38 88.4

1. 72%2. 437.7 378.48 11.15 87.1

1. 29%2. 477.9 378.49 10.14 87.1

1. 61%2. 560.2 378.50 11.18 87.1

1. 25%2. 480.0 378.51 10.18 87.1

1. 51%2. 466.0 378.52 12.2 87.1

1. 32%2. 380.9 378.53 10.19 87.1

1. 14%2. 461.4 378.54 11.1 87.1

1. 41%2. 463.9 378.55 11.2 87.1

1.  5%2. 409.9 378.56 10.20 87.1

1. 70%2. 478.1 378.57 10.49 87.1

1. 17%2. 421.9 378.58 10.15 87.1

1. 51%2. 582.1 378.59 10.46 87.1

1. 18%2. 477.9 378.60 11.16 88.4

1. 54%2. 455.1 378.61 10.21 87.1

1. 84%2. 485.9 378.62 10.40 87.1

1.  4%2. 506.1 378.65 2.8 87.1

1. 34%2. 480 378.66 10.22 87.1

1. 16%2. 486.0 378.67 2.10 87.1

1. 44%2. 545 378.68 10.23 87.1

1. 26%2. 493.9 378.69 2.14 87.1

1. 60%2. 437.9 378.70 10.24 87.1

1. 64%2. 469.9 378.71 10.18 88.4

1. 64%2. 471.1 378.72 10.39 88.4

1. 41%2. 451.7 378.73 10.30 87.1

1. 60%2. 464.0 378.74 10.25 87.1

1. 63%2. 470.1 378.75 10.26 87.1

1. 10%2. 448.0 378.76 10.50 87.1

1.  5%2. 477.0 378.77 10.42 88.4

1. 57%2. 467.7 378.78 11.17 87.1

1. 75%2. 478.0 378.79 2.9 87.1

1. 21%2. 561 378.80 10.43 87.1

1. 69%2. 437.9 378.81 10.41 87.1

1.  3%2. 436.0 378.82 10.44 87.1

1. 90%2. 454.0 378.83 10.13 88.4

1. 29%2. 524.1 378.84 10.45 88.4

1. 46%2. 511.7 378.86 10.37 87.1

1. 53%2. 452.0 378.88 10.47 87.1

1. 61%2. 506.1 378.89 10.16 87.1

1. 30%2. 568.1

Example 378.90

The above compound from Preparative Example 378.68 was stirred with 4NHCl/dioxane to yield the product (23%, MH+=437.9).

Example 378.91

Using the procedure set forth in Preparative Example 2, Step A, butusing Preparative Example 2.16 and Preparative Example 2.15, the titlecompound was prepared (20%, MH+=472.9).

Examples 379–393

Following the procedure set forth in Example 210 but using the aminefrom the Preparative Example indicated and the ethoxy squarateintermediate from Preparative Example 87, the following cyclobutenedioneproducts were obtained.

1. Yield (%) Ex. Aniline Product 2. (MH⁺) 379 109

1. 29%2. 436.0 380 105

1.  6.3%2. 550.0 381 106

1. 12%2. 557.0 382 107

1.  8.6%2. 573.0 383 143

1.  3.2%2. 497.0 384 135

1. 36%2. 529.0 385 130

1. 33%2. 506.1 387 145

1. 27%2. 449.1 388 140

1. 25%2. 477.0 389 98

1. 66%2. 542.1 390 96

1. 60%2. 545.0 391 97

1. 66%2. 540.1 392 100

1. 47%2. 512.1 393 99

1. 60%2. 528.1

Examples 394–404.4

Following the procedure set forth in Example 261 but using the aminesfrom the Preparative Examples indicated in the table below and thecyclobutenedione derivative from Preparative Example 19, the followingcyclobutenedione products were obtained as racemic mixtures.

1. Yield (%) Prep Ex. 2. MH⁺ Ex. of Amine Product 3. mp (° C.) 394 147

1. 64%2. 358.13. 137 395 148

1. 23%2. 372.13. 126 396 149

1. 94%2. 386.13. 108 397 150

1. 86%2. 386.13. 134 398 146

1. 87%2. 420.13. 136 399 151

1. 84%2. 434.13. 129 400 152

1. 90%2. 372.13. 154 401 153

1. 86%2. 386.13. 156 402 154

1. 90%2. 400.13. 153 403 155

1. 912. 400.13. 153 404 156

1. 83%2. 448.13. 138 404.1

1. 30%2. 426.13. 132 404.2

1. 74%2. 412.13. 127 404.3

1. 73.4%2. 372.13. 128 404.4

1. 72%2. 372.13. 128

Example 405

To a solution of the amine from Preparative Example 75.1 (11.3 g) inEtOH (100 mL) at room temperature was added the product from PreparativeExample 19 (16.4 g) in one portion. The resulting mixture was stirred atreflux overnight and then concentrated under reduced pressure. The cruderesidue was redissolved in CH₂Cl₂ (80 mL) and was washed with 10% KH₂PO₄(120 mL). The solid precipitate that was generated was filtered, washedwith water and dried under vacuo. The residue was recrystallized frommethanol-methylene chloride to give a cream colored solid (16 g, 75%yield). (mp 105–108° C., MH⁺398.1).

Examples 1101–1112.10

If one were to follow the procedure set forth in Example 210 but usingthe ethoxysquarate from the Preparative Example indicated and the aminesfrom the Preparative Example indicated in the Table below, the followingcyclobutenedione products can be obtained.

Prep Ex of Prep Ex of Ex. Amine Squarate Product 1101  15 87

1102  15 88

1103  16 87

1104  16 88

1105  17 87

1106  17 88

1107  18 87

1108  18 88

1109 157 87

1110 157 88

1111 158 87

1112 158 88

1112.1 500.3 or500.4 88.1

1112.2 500.1 or500.2 88.1

1112.3 500.5 19

1112.4  75.9 23.11

1112.5  10.19 88.4

1112.6  75.44 23.14

1112.7  75.49 23.14

1112.8  75.50 23.14

1112.9  75.44 500.6

1112.10  75.49 500.6

Examples 1120.1–1120.12

Following the procedure set forth in Example 210 but using the aminefrom the Preparative Example indicated and the ethoxy squarateintermediate from the Preparative Example indicated, the followingcyclobutenedione products were obtained.

Prep Ex 1. Yield (%) Prep Ex of of 2. MH⁺ Ex. Amine Squarate Product 3.mp (° C.) 1120.1 156.16 87

1. 9%2. 393.13. 154–158 1120.2

88.1

1. 55%2. 355.13. 199–201 1120.3 156.12 88.1

1. 37%2. 355.13. 210–213 1120.4

88.1

1. 30%2. 391.13. 70–73 1120.5 156.14 88.1

1. 73%2. 4663. 105–108 1120.6

88.1

1. 21%2. 3913. 79–82 1120.7

88.1

1. 15%2. 3693. 167–170 1120.8

88.1

1. 47%2. 3543. 121–124 1120.9

88.1

1. 15%2. 3563. 200–202 1120.10

88.1

1. 25%2. 4683. 154–156 1120.11 156.13 88.1

1. 57%2. 4043. 92–94 1120.12 156.15 88.1

1. 61%2. 3513. 155–157

Example 1125

Step A

If one were to use a similar procedure to that used in PreparativeExample 13.3 Step B, except using the hydroxy acid from Bioorg. Med.Chem. Lett. 6(9), 1996, 1043, one would obtain the desired methoxycompound.

Step B

If one were to use a similar procedure to that used in PreparativeExample 13.19 Step B, except using the product from Step A above, onewould obtain the desired compound.

Step C

If one were to use a similar procedure to that used in Synth. Commun.1980, 10, p. 107, except using the product from Step B above andt-butanol, one would obtain the desired compound.

Step D

If one were to use a similar procedure to that used in Synthesis, 1986,1031, except using the product from Step C above, one would obtain thedesired sulfonamide compound.

Step E

If one were to use a similar procedure to that used in PreparativeExample 13.19 Step E, except using the product from Step D above, onewould obtain the desired compound.

Step F

If one were to use a similar procedure to that used in PreparativeExample 19, except using the product from Step E above and addingpotassium carbonate as base, one would obtain the desired compound.

Step G

If one were to follow the procedure set forth in Example 210, exceptusing the product from Step F above and the amine from PreparativeExample 75.9, then one would obtain the title compound.

Example 1130

Step A

If one were to treat the product from Step C of Example 1125 with BuLi(2.2 eq.) in THF followed by quenching of the reaction mixture withN,N,-dimethylsulfamoyl chloride (1.1 eq.) then one would obtain

Step B

If one were to use the product of Step A above and one were to followSteps E, F and G of Example 1125, except using the amine fromPreparative Example 75.49 in Step G, then one would obtain the titlecompound.

Example 1131

Step A

To a solution of 3-methoxythiophene (3 g) in dichloromethane (175 mL) at−78° C. was added chlorosulfonic acid (8.5 mL) dropwise. The mixture wasstirred for 15 min at −78° C. and 1.5 h at room temp. Afterwards, themixture was poured carefully into crushed ice, and extracted withdichloromethane. The extracts were washed with brine, dried overmagnesium sulfate, filtered through a 1-in silica gel pad. The filtratewas concentrated in vacuo to give the desired compound (4.2 g).

Step B

The product from Step A above (4.5 g) was dissolved in dichloromethane(140 mL) and added with triethylamine (8.8 mL) followed by diethyl aminein THF (2M, 21 mL). The resulting mixture was stirred at roomtemperature overnight. The mixture was washed with brine and saturatedbicarbonate (aq) and brine again, dried over sodium sulfate, filteredthrough a 1-in silica gel pad. The filtrate was concentrated in vacuo togive the desired compound (4.4 g).

Step C

The product from Step B above (4.3 g) was dissolved in dichloromethane(125 mL) and cooled in a −78° C. bath. A solution of boron tribromide(1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirredfor 4 h while the temperature was increased slowly from −78° C. to 10°C. H₂O was added, the two layers were separated, and the aqueous layerwas extracted with dichloro-methane. The combined organic layer andextracts were washed with brine, dried over magnesium sulfate, filtered,and concentrated in vacuo to give 3.96 g of the desiredhydroxy-compound.

Step D

The product from step C above (3.96 g) was dissolved in 125 mL ofdichloromethane, and added with potassium carbonate (6.6 g) followed bybromine (2 mL). The mixture was stirred for 5 h at room temperature,quenched with 100 mL of H₂O. The aqueous mixture was adjusted to pH˜5using a 0.5N hydrogen chloride aqueous solution, and extracted withdichloromethane. The extracts were washed with brine, dried over sodiumsulfate, and filtered through a celite pad. The filtrate wasconcentrated in vacuo to afford 4.2 g of the desired bromo-compound.

Step E

The product from Step D (4.2 g) was dissolved in 100 mL of acetone andadded with potassium carbonate (10 g) followed by iodomethane (9 mL).The mixture was heated to reflux and continued for 3.5 h. After cooledto room temperature, the mixture was filtered through a Celite pad. Thefiltrate was concentrated in vacuo to a dark brown residue, which waspurified by flash column chromatography eluting withdichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desired product.

Step F

The product from step E (2.7 g) was converted to the desired iminecompound (3 g), following the similar procedure to that of PreparativeExample 13.19 step D.

Step G

The imine product from step F (3 g) was dissolved in 80 mL ofdichloromethane and cooled in a −78° C. bath. A solution of borontribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. Themixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane. The organic layer and extracts were combined,washed with brine, and concentrated to an oily residue. The residue wasdissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) andhydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. Themixture was poured into an aqueous mixture of sodium hydroxide (1.0 Maq, 50 mL) and ether (100 mL). The two layers were separated. Theaqueous layer was washed with ether three times. The combined etherwashings were re-extracted with H₂O once. The aqueous layers werecombined, washed once with dichloromethane, adjusted to pH˜6 using 3.0 Mand 0.5 M hydrogen chloride aqueous solutions, and extracted withdichloromethane. The organic extracts were combined, washed with brine,dried over sodium sulfate, and concentrated in vacuo to give 1.2 g ofdesired amine compound.

Step H

The product from step F (122 mg) was stirred with diethyoxysquarate(0.25 mL) and potassium carbonate (75 mg) in 5 mL of ethanol at roomtemperature for 5 h. The mixture was diluted with dichloromethane,filtered through a Celite pad, and concentrated to an oily residue,which was separated by preparative TLC (CH₂Cl₂-M⁻OH=15:1, v/v) to give91 mg of the desired product.

Step I

Following the procedure set forth in Example 210, and using the aminefrom Preparative Example 75.9, the product (43 mg) from Step H wasconverted to the desired compound (20 mg).

Preparative Example 600

Step A

Following the procedure set forth in Preparative Example 13.19 Step D,the imine was prepared from the known bromoester (1.0 g) to yield 1.1 g(79%) as a yellow solid.

Step B

The product of step A (0.6 g) was reacted following the procedure setforth in Preparative Example 13.19 Step E to give the amine product 0.19g (64%).

Step C

The product of Step B (1.0 g) was reacted following the procedure setforth in Preparative Example 13.19 Step B to give the acid as yellowsolid 0.9 g (94%).

Step D

The product of Step C (0.35 g) was reacted following the procedure setforth in Preparative Example 13.19 Step E to give the amino acid asyellow solid 0.167 g (93%).

Preparative Example 601

Step A

To a solution of 2-methyl furan (1.72 g) in ether was added BuLi (8.38mL) at −78° C. and stirred at room temperature for half an hour. Thereaction mixture again cooled to −78° C. and quenched with cyclopropylamide 1 and stirred for two hours at −78° C. and slowly warmed to roomtemperature. The reaction mixture stirred for three hours at roomtemperature and quenched with the addition of saturated ammoniumchloride solution. The mixture was taken to a separatory funnel, washedwith water, brine and dried over anhydrous sodium sulfate. Filtrationand removal of solvent afforded the crude ketone, which was purified byusing column chromatography to afford the ketone 3.0 g (87%) as a paleyellow oil.

Step B

To a solution of ketone (1.0 g) from Step A above in THF (5.0 mL) at 0°C. was added R-methyl oxazoborolidine (1.2 Ml, 1M in toluene) dropwisefollowed by addition of a solution of borane complexed with dimethylsulfide (1.85 mL, 2M in THF). The reaction mixture was stirred for 30minutes at 0° C. and than at room temperature for one hour. The reactionmixture was cooled to 0° C. and MeOH was added carefully. The mixturewas stirred for 20 minutes and was concentrated under reduced pressure.The residue was extracted with ether, washed with water, 1M HCl (10 mL),saturated sodium bicarbonate (10.0 mL) water and brine. The organiclayer was dried over anhydrous sodium sulfate, filtered and removal ofsolvent afforded the crude alcohol which was purified by silica gelchromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

Preparative Example 602

Step A

An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) wasmixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours. Aftercooling the reaction mixture, water (10 mL) was added, followed bysaturated sodium carbonate solution until it becomes alkaline. Thereaction mixture was extracted with ether several times and the combinedether layer was washed with water, brine and dried over anhydrous sodiumsulfate. Filtration and removal of solvent afforded the crude ketone,which was purified by using silica gel chromatography to afford theketone 0.9 g (43%) as a yellow oil.

Step B

The title alcohol was obtained following a similar procedure set forthin Preparative Example 601.

Preparative Example 603

To a solution of 5-methyl furan-2-aldehyde (1.0 g) and3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indiumpowder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture wasstirred over night, diluted with water and extracted with ether. Theether layer was washed with water, brine and purified by silica gelchromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 604–611

Following a similar procedure set forth in Preparative Examples 13.25 or601 the following Alcohols were prepared.

Prep Ex Furan Electrophile Alcohol Yield 604

86% 605

69% 606

84% 607

82% 608

60% 609

65% 610

82% 611

89%

Preparative Examples 620–631

Following a similar procedure set forth in Preparative Examples 13.25the following Amines were prepared from the corresponding Alcohols.

Prep Ex ALCOHOL AMINE % YIELD 620

28% 621

58% 622

69% 623

81% 624

82% 625

45% 626

57% 627

58% 628

54% 629

53% 630

50% 631

82

Preparative Examples 640–641

Following the procedures set forth in Preparative Example 19 but usingthe amine from the Preparative Example indicated in the Table below, thecyclobutenedione intermediates were obtained.

Amine from 1. Yield (%) Prep Ex. Prep Ex. Product 2. MH⁺ 640 600 Step B

1. 60%2. 138 641 600 Step D

1. 66%2. 138

Examples 1200–1211

Following the procedure set forth in Example 261 but using thecommercially available amine or the prepared amine from the PreparativeExample indicated in the table below, the following cyclobutenedioneproducts were obtained.

1. Yield (%) 2. MH⁺ Ex. Amine Product 3. mp (° C.) 1200

1. 61.3%2. 451.43. 108.6 1201

1. 54%2. 439.53. 117.8 1202

1. 80%2. 439.53. 128–131.8 1203

1. 75%2. 423.43. 118–119 1204

1. 74%2. 447.43. 108–111 1205

1. 42%2. 415.423. 136–140 1206

1. 46%2. 423.43. 114–117 1207

1. 35%2. 433.13. 123–128 1208

1. 42%2. 423.43. 118–121 1209

1. 51%2. 415.43. 112–117 1210

1. 44%2. 415.4%3. 115–120 1211

1. 48%2. 445.43. 105–110

Examples 1300–13011

Following the procedure set forth in Example 261 but using thecommercially available amine in the table below and the cyclobutenedioneintermediate from the Preparative Example indicated, the followingcyclobutenedione products were obtained.

1. Yield (%) Prep. 2. MH⁺ Ex. Amine Ex. Product 3. mp (° C.) 1300

640

1. 35%2. 390.43. 100 1301

641

1. 78%2. 390.43. 130 1302

23.9

1. 48%2. 483.43. 116 1303

23.9

1. 46%2. 443.53. 106 1304

23.9

1. 40%2. 445.543. 102 1305

23.9

1. 51%2. 413.43. 98 1306

23.9

1. 78%2. 405.53. 246 1307

23.9

1. 83%2. 439.53. 129 1308

23.15A

1. 11%2. 519.473. 123 1309

23.15A

1. 47%2. 4753. 113 1310

640

1. 55%2. 496.13. 123–125 1311

640

1. 74%2. 468.13. 116–118

Preparative Example 1001

Step A

Oxalyl chloride (3 mL, 34.27 mmol) was added dropwise to a mixture of2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6.81 mmol) (preparedaccording to known method, see: EP0897904B1), N,N-dimethylformamide (0.3mL), and dichloromethane (40 mL) with stirring at rt. The reactionmixture was stirred overnight. Evaporation of solvent and excess oxalylchloride and drying under vacuum afforded2-methoxy-6-(trifluoromethyl)benzoyl chloride as a solid, which was usedwithout purification.

Step B

A solution of 2-methoxy-6-(trifluoromethyl)benzoyl chloride (ca. 6.81mmol) from Step A above in dichloromethane (20 mL) was added dropwise toa mixture of 4-(dimethylamino)pyridine (42 mg, 0.34 mmol), triethylamine(2.8 mL, 20.09 mmol), and 2 M dimethylamine solution in tetrahydrofuran(7 mL, 14 mmol), and dichloromethane (30 mL) with stirring at rt. Thereaction mixture was stirred overnight. A mixture of dichloromethane andwater was added. The organic phase was separated, washed with 1N HClsolution, water, and saturated sodium bicarbonate solution andconcentrated. The residue was purified by column chromatography (ethylacetate:hexanes, 3:1 v/v) to give the product as a white solid (1.24 g.74% over two steps).

Step C

A mixture of the amide from Step B above (1.8 g, 7.28 mmol), carbontetrachloride (25 mL), and iron powder (305 mg, 5.46 mmol) was cooled to0° C. Bromine (0.94 mL, 18.34 mmol) was added dropwise with stirring.After addition, the mixture was stirred at rt for 1 h and at 50° C. for3 h. The mixture was cooled to rt, diluted with dichloromethane, andslowly poured to a cold 10% NaHSO₃ solution. After stirring at rt for0.5 h, the organic layer was separated and concentrated to give theproduct as a white solid (2.26 g, 95%).

Step D

Concentrated sulfuric acid (10 mL) was added dropwise to a flask chargedwith the bromide from Step C above (600 mg, 1.84 mmol) at 0° C. withstirring. A mixture of nitric acid (0.2 mL, 4.76 mmol) and concentratedsulfuric acid (0.3 mL) was then added dropwise. After addition, themixture was stirred at rt for 3 h. The mixture was added to ice-water,neutralized with 15% NaOH solution to pH 7, and extracted withdichloromethane. The organic layer was concentrated to give the productas a white solid (621 mg, 91%). mp 92° C., m/e 371 (MH⁺).

Step E

A solution of the compound from Step D above (1.2 g, 3.23 mmol) indichloromethane (50 mL) was cooled to −75° C. 1 M BBr₃ solution indichloromethane (7.5 mL, 7.5 mmol) was added dropwise with stirring. Themixture was stirred at −75° C. for 2 h. The mixture was added toice-water. After stirring at rt for 0.5 h, the mixture was extractedwith dichloromethane. The organic was concentrated and the residue waspurified by column chromatography (dichloromethane-methanol, 9:1 v/v) togive the product as a yellow solid (1.05 g, 91%). m/e 357 (MH⁺).

Step F

A mixture of the compound from Step E above (1.08 g, 3.02 mmol),methanol (30 mL), and 10% Pd—C (250 mg) was subjected to hydrogenationat 50 psi at rt for 6 h. The mixture was filtered through a layer ofCelite. The filtrate was concentrated to give the title compound as apale yellow solid (930 mg, 96%). mp 132° C., m/e 249.

Preparative Example 1002

Step A

To a cooled (−70° C.) etherial (45 mL dry) solution of 3-bromothiophene(3.8 mL) was added BuLi (30 mL of 1.6M in hexane) dropwise, and themixture was stirred at −70° C. for 20 min. Acetophenone (4.6 mL) inether (6 mL) was added dropwise with stirring at −70° C. After 3 hrs,the mixture was warmed to RT and sat. NH₄Cl (aq) was added and themixture was extracted with ether. The organic phase was dried (Na₂SO₄)and concentrated in vacuo to give the title compound which was used inStep B without further purification.

Step B

The crude product from Step A above was stirred with oxalic acid (0.375g) at 70° C. under reduced pressure for 3 hr, then cooled to RT andextracted with ether. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo to give the product as a pale yellow liquid (5.7g, 78% for Steps A–B)

Step C

To the product from Step B above (4.2 g) diluted with dichloromethane(30 mL) and containing triethylsilane (6 mL) was added TFA (3 mL) indichloromethane (7.5 mL). After stirring at RT for 10 min, the mixturewas concentrated in vacuo to give the product as a colorless liquid(4.61 g, 80%).

Step D

To an etherial (3.5 mL dry) solution of the thiophene product (1.5 g)from Step C above was added BuLi (3.2 mL of 2.5M), and the mixture washeated at reflux for 15 min, cooled to RT, and DMF (0.8 mL) in ether(3.5 mL) was added dropwise. After stirring for 30 min, sat. NH₄Cl (aq)was added and the mixture was extracted with ether. The organic phasewas dried (Na₂SO₄) and concentrated in vacuo to give the title compound(1.71 g, 98%).

Preparative Example 1003

Step A

The aldehyde (0.50 g) was combined with ethylene glycol (1 mL), benzene(40 mL) and pTSA monohydrate (30 mg) and stirred at reflux for 20 hr.Cool to room temperature, add EtOAc and sat. NaHCO₃ (aq) solution,separate the organic phase, concentrate in vacuo, and purify by silicagel chromatography (EtOAc-Hex, 1:4) to give a colorless liquid (60 mg)

Step B

The product from Step A above (0.607 g) was stirred at 45° C. overnightwith 1N NaOH (aq), then cooled to room temperature, acidified with 3NHCl and extracted with EtOAc. Washing with brine and concentration invacuo gave a solid (5.0 g).

Step C

Following a similar procedure as that used in Preparative Example 1,except using the product from Step B above and dimethylamine in THF(2M), the product was obtained (1.21 g crude).

Step D

The product from Step C above was dissolved in THF and stirred with 0.3NHCl (aq) and stirred at RT for 4 hr. Concentration in vacuo gave a paleyellow oil (1.1 g, 67%).

Preparative Example 1004

Step A

To a cooled (−78° C.) solution of methoxybenzofuran-2-carboxylic acid (1g) was added DIBAL (30 mL, 1M in THF). After stirring for 20 min, themixture was warmed to RT and stirred for 4 hr, then poured into sat.NH4Cl (aq) (35 mL). After stirring at RT for 20 min, 6M HCl (aq) wasadded and the mixture was extracted with EtOAc, the organic phase driedand then concentrated in vacuo. Purification by silica gelchromatography (EtOAc-hexane, 3:7) afforded the alcohol as a solid (0.4g, 97%).

Step B

A mixture of the product from Step A above (0.9 g), EtOAc (50 mL) andMnO2 (5.2 g) was stirred at RT for 22 h, then filtered and concentratedin vacuo. The solid was redissolved in EtOAc (50 mL), MnO2 (5.2 g) wasadded and the mixture was stirred for 4 additional hrs. Filtration,concentration and silica gel purification (EtOAc-Hexane, 1:3) gave thetitle compound as a solid (0.60 g, 67%).

Preparative Example 1005

Following a similar procedure as that detailed in Preparative Example1004, except using 5-chlorobenzofuran-2-carboxylic acid (1.5 g), thetitle compound was obtained (solid, 0.31 g, 24%).

Preparative Example 1006

Step A

The sulfonyl chloride from Preparative Example 13.29 Step A (1.5 g) wasstirred with AlCl3 and benzene for 15 min at 20° C. Treatment with NaOH,extraction with Et₂O, concentration in vacuo, and purification by columnchromatography (silica, hexane-EtOAc, 5:2) gave the phenylsulfone (1.5g, 84%, MH⁺=255).

Step B

Following similar procedures as those used in Preparative Example 13.29Steps C–G, except using the sulfone from Step A above, the titlecompound was prepared (0.04 g, 27%, MH⁺=256).

Preparative Examples 1007–1029

Following a similar procedure set forth in Preparative Example 19.1 ofWO 02/083624, published Oct. 24, 2002, or Preparative Example 19.2, butusing the Amine (Anilines) listed in the Table below, the followingsquarate intermediates were prepared.

1. Yield (%) Example Amine/Aniline Product 2. (M + 1)⁺ 1007

1. 95%2. 359 1008

1. 99%2. 333 1009

1. 99%2. 333 1010

1. 99%2. 311 1011

1. 99%2. 275 1012

1. 99%2. 333 1013

1. 72%2. 353.0 1014

1. 60%2. 355.1 1015

1. 70%2. 303.1 1016

1. 45%2. 327.0 1017

1. 70%2. 367.0 1019

1. 32%2. 409 1020

1. 48%2. 466 1021

1. ~60%(crude) 1022

1. 21% 1023

1. 45%2. 389 1024

1. 30%2. 380 1027

1. 44%2. 264 1028

1. 56%2. 278 1029

1. 47%2. 292

Preparative Example 1030

Step A

The product of Preparative Example 34.18 Step B (2 g, 8 mmol) wasstirred with morpholine (0.9 mL, 10.29 mmol) and K2CO3 (2.2 g, 15.9mmol) in 50 mL of acetone at RT to obtain the morpholinobutylfuranderivative (1.22 g,73%).

Step B

Following a similar procedure as in Preparative Example 34.18 Step D,but using the product (1.2 g) from Step A above, the title aldehyde wasprepared (0.9 g,66%, 1:0.7 regioisomeric mixture).

Preparative Example 1031

A solution of 5-bromobenzofuran (950 mg, 4.82 mmol) inanhydrous-ether.(12 mL) was cooled to −78° C. 1.7 M tert-BuLi solutionin pentane (6 ml, 10.2 mmol) was added dropwise under argon. Afteraddition, the mixture was stirred at −78° C. for 20 min, followed byaddition of a mixture of DMF (0.8 mL) and ether (1 mL). The mixture wasallowed to warm to rt and stirred for 0.5 h. Ethyl acetate was added.The mixture was poured to saturated ammonium chloride solution. Theorganic layer was separated and concentrated. The residue was purifiedby column chromatography (ethyl acetate-hexanes, 1:5 v/v) to give thetitle compound as a pale yellow solid (490 mg, 70%).

Preparative Examples 1040–1054

Following the procedure set forth in Preparative Example 64 of WO02/083624, published Oct. 24, 2002, but using the commercially available(or prepared) aldehyde, aminoalcohols, and organolithium reagents in theTable below, the optically pure amine products in the Table below wereobtained.

Prep. Amino Organo- 1. Yield (%) Ex. Aldehyde Alcohol lithium Product 2.(M + 1)⁺ 1040

EtLi

1. 24%2. 267 1041

EtLi

1. 94%2. 176(m/e) 1042

EtLi

1. 67%2. 229(M − 16) 1043

i-PrLi

1. 60%2. 151 [M −16] 1044

EtLi

1. 74%2. 194(M − 16) 1045

EtLi

1. 33%2. 165 [M −NH2]⁺ 1046

EtLi

1. 312. 179 [M −NH2]⁺ 1047

t-BuLi

1. 31%2. 188 1048

t-BuLi

1. 10%2. 154 1049

EtLi

1. 73%2. 137 [M −NH2]⁺ 1051

t-BuLi

1. 17% 1054

t-BuLi

1. 79%2. 151(M − 16)

Preparative Examples 1100–1126

Following the procedure set forth in Preparative Example 34 of WO02/083624, published Oct. 24, 2002, but using the commercially availablealdehydes and Grignard/Organolithium reagents listed in the Table below,the amine products were obtained.

Prep. Organo-metallic 1. Yield (%) Ex. Aldehyde Reagent Product 2. (M +1)⁺ 1100

t-BuLi

1. 83%2. 190 (M − 16) 1101

t-BuLi

1. 46%2. 204 1102

t-BuLi

1. 48%2. 194 1103

t-BuLi

1. 51%2. 194 1104

t-BuLi

1. 12%2. 238 1105

t-BuLi

1. 39%2. 234 1106

t-BuLi

1. 44%2. 194 (m/e) 1107

t-BuLi

1. 57%2. 150 (M − 16) 1108

t-BuLi

1. 31%2. 224 1109

t-BuLi

1. 11%2. 224 1110

t-BuLi

1. 57%2. 224 1111

t-BuLi

1. 21%2. 224 1112

c-Pentyl-Li

1. 58%2. 190 1113

t-BuLi

1. 20%2. 248 1114

t-BuLi

1. 24%2. 232 1115

EtLi

1. 32%2. 177 (M −NH2) 1116

t-BuLi

1. 26%2. 205 (M −NH2) 1117

t-BuLi

1. 50%2. 190 (M −NH2) 1118

t-BuLi

1. 29%2. 200 1119

t-BuLi

1. 28%2. 232 1120

t-BuLi

1. 76%2. 224 1121

t-BuLi

1. 40%2. 206 1122

t-BuLi

1. 38%2. 236 1123

t-BuLi

1. 70%2. 192 1124

t-BuLi

1. 81%2. 204 1125

t-BuLi

33% 1126

t-BuLi

50%

Preparative Examples 1200–1203

Following the procedure set forth in Preparative Example 13.29 but usingthe commercially available amines, the hydroxyaminothiophene productslisted in the Table below were obtained.

Prep. 1. Yield (%) Ex. Amine Product 2. (M + 1)⁺ 1200

1. 3%2. 342 1201

1. 41%2. 265 1202

1. 17%2. 237 1203

1. 1%

Preparative Example 1300

The title compound from Preparative Example 13.32 (0.35 g) was treatedwith concentrated sulfuric acid (3 mL) for 6 hrs, then poured on ice,and the pH adjusted to 4 with NaOH. Extraction with EtOAc, and drying ofthe organic phase over Na₂SO₄ gave the title compound (159 mg, 64%,MH⁺=223).

Preparative Example 1301

Step A

Following the procedure set forth in Preparative Example 605 but usingthe commercially available fluoroisopropylester, the alcohol product wasobtained (1.2 g, 84%, M-OH=155).

Step B

Following the procedure set forth in Preparative Example 625 but usingthe alcohol from Step A above, the amine product was obtained (350 mg,35%, M-NH2=155).

Preparative Example 1302

Step A

Following a similar procedure as that used in Preparative Example 13.29Step B, except using the commercially available arylsulfonylchloride(0.15 g) and diethylamine (2.2 eq), the dimethylsulfonamide was obtained(0.12 g, 71%, MH⁺=323).

Step B

Following a similar procedure as that used in Preparative Example 13.29Step C, except using the product from Step A above (0.12 g), the phenolwas obtained (0.112 g, 98%).

Step C

Following a similar procedure as that used in Preparative Example 10.55Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above (0.112 g), the title compound was obtained(0.1 g, 99%, MH⁺=245).

Preparative Example 1303

Following a similar procedure as that used in Preparative Example 1302Steps A–C, except using piperidine in Step A (0.078 g) instead ofdiethylamine, the title compound was obtained (0.070 g, 35%, MH⁺=257).

Preparative Example 1304

Following a similar procedure as that used in Preparative Example 1302Steps A–C, except using dimethylamine (2M in THF) in Step A instead ofdiethylamine, the title compound was obtained (1.92 g, 72%, MH⁺=217).

Preparative Example 1305

Step A

Following a similar procedure as that used in Preparative Example 1302Step A, except using the phenethylamine indicated (4.99 g), the productwas obtained (5.96 g, 86%, MH⁺=210).

Step B

The compound from Step A above (5.0 g) was added to 30 g of PPA at 150°C. and the resulting mixture stirred for 20 min, before being poured onice and extracted with dichloromethane. The organic phase was dried overMgSO4, concentrated in vacuo and purified by silica gel chromatography(EtOAc:MeOH, 95:5) to give the product (0.5 g, 9%).

Step C

Following a similar procedure as that used in Preparative Example 13.3Step D, of WO 02/083624, published Oct. 24, 2002, except using thecompound from Step B above (0.14 g), the product was obtained (0.18 g,87%, MH⁺=256).

Step D

Following a similar procedure as that used in Preparative Example 11Step B, of WO 02/083624, published Oct. 24, 2002, except using thecompound from Step C above (0.18 g), the product was obtained (0.17 g).

Step E

Following a similar procedure as that used in Preparative Example 13.3Step B, of WO 02/083624, published Oct. 24, 2002, except using thecompound from Step D above (0.17 g), the product was obtained (0.17 g,95%, MH⁺=315).

Step F

Following a similar procedure as that used in Preparative Example 13.29Step C, except using the product from Step E above (0.17 g), thenitrophenol was obtained (0.165 g, 99%, MH⁺=303).

Step G

Following a similar procedure as that used in Preparative Example 10.55Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step F above (0.165 g), the title compound was obtained(0.128 g, 86%, MH⁺=193).

Preparative Example 1306

Step A

Following a similar procedure as that used in Preparative Example 11Step B, of WO 02/083624, published Oct. 24, 2002, except using thelactam (0.179 g), the title compound was obtained (0.25 g, 25%).

Step B

Following a similar procedure as that used in Preparative Example 13.29Step C, except using the product from Step A above (0.055 g), the phenolwas obtained (0.045 g, 99%).

Step C

Following a similar procedure as that used in Preparative Example 10.55Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above (0.045 g), the title compound was obtained(0.022 g, 57%, MH⁺=179).

Preparative Example 1307

Following a similar procedure as that used in Preparative Example 2, ofWO 02/083624, published Oct. 24, 2002, except using3(R)-hydroxypyrrolidine HCl (1.36 g), the title compound was obtained(2.25 g, 89%).

Preparative Example 1308

Following a similar procedure as that used in Preparative Example 2, ofWO 02/083624, published Oct. 24, 2002, except using morpholine, thetitle compound was obtained (3.79 g).

Preparative Example 1309

Step A

Following a similar procedure as that used in Preparative Example 13.29Step B, except using the commercially availablenitrophenylsulfonylchloride and diethylamine (2.2 eq), thedimethylsulfonamide was obtained (90%, MH⁺=231).

Step B

Following a similar procedure as that used in Preparative Example 10.55Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above, the title compound was obtained (45%,MH⁺=201).

Preparative Example 1310

Step A

Following a similar procedure as that used in Preparative Example 13.29Step B, except using the commercially available nitrobenzoylchloride andthe commercially available amine indicated, the benzamide was obtained(13%, MH⁺=253).

Step C

Following a similar procedure as that used in Preparative Example 10.55Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above, the title compound was obtained (94%,MH⁺=223).

Preparative Example 1311

Step A

To a benzene (20 mL) solution of methoxythiophenesulfonylchloride (1.5g) was added AlCl₃ (2.0 g) at RT. After 15 min, the mixture was added to0.1N HCl (aq) with stirring, then extracted with Et₂O. Washing theorganic phase with bring, drying over MgSO₄, concentration in vacuo andpurification by silica gel chromatography (Hexane:EtOAc, 5:2) gave thetitle compound (1.5 g, 84%).

Step B

Following a similar procedure as that used in Preparative Example 13.29Steps C–G, except using the product from Step A above, the titlecompound was obtained (3%, MH⁺=380).

Preparative Example 1312

Step A

Following a similar procedure as that used in Preparative Example 1311Step A, except using the commercially available sulfonylchloride, thediphenylsulfone was obtained (880 mg, 80%).

Step B

Following a similar procedure as that used in Preparative Example 11Step B, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step A above, the title compound was obtained (0.90 g,97%).

Step C

Following a similar procedure as that used in Preparative Example 10.55Step C, of WO 02/083624, published Oct. 24, 2002, except using theproduct from Step B above (0.16 g), the title compound was obtained(0.106 g, 95%).

Preparative Example 1313

Step A

Following a similar procedure as that used in Preparative Example 1311Step A, except using the commercially available phenol (2 g), thenitroacid was obtained (˜13 mmol).

Step B

Oxallyl chloride (3.5 mL) and two drops of DMF was added to the productfrom Step A above (˜13 mmol) dissolved in dichloromethane (100 mL).After stirring at RT overnight, the mixture was concentrated in vacuo,diluted with dichloromethane (50 mL), cooled to 0° C. Dimethylamine inTHF (20 mL of 2N) and TEA (8 mL) were added. After 3 hr of stirring, themixture was concentrated in vacuo, aq NaOH (1M) was added, and themixture was extracted with dichloromethane. The pH of the aq is layerwas adjusted to pH=2 using 6N HCl (aq), and extracted withdichloromethane. The combiuned organic extracts were washed with brine,dried, concentrated in vacuo, and the product purified by silica gelchromatography (700 mL dichloromethane/20 mL MeOH/1 mL AcOH) to give thetitle compound (800 mg, 27% for two steps).

Step C

Following a similar procedure as that used in Preparative Example 10.55Step C, WO 02/083624, published Oct. 24, 2002, except using the productfrom Step B above (780 mg), the title compound was obtained (0.46 g,68%).

Examples 2001–2088

Following a similar procedure set forth in Example 210, of WO 02/083624,published Oct. 24, 2002, but using the cyclobutenedione intermediate andamine indicated in the Table below, the following cyclobutenedioneproducts were obtained. See WO 02/083624, published Oct. 24, 2002, forPreparative Examples 19, 19.2, 22, 23.14 and 87.1.

Prep Ex of intermediate 1. Yield (%) Example and Amine Product 2. (M +1)⁺ 2001 19 and

3. 65%4. 465 2002 19 and

1. 5%2. 422 2003 19 and

1. 47%2. 462 2004 19 and

1. 74%2. 452 2005 19 and

1. 71%2. 452 2006 1007 and

1. 18%2. 494 2007 19 and

1. 36%2. 434 2008 19 and

1. 19%2. 440 2009 19 and

1. 45%2. 504 2010 19 and

1. 57%2. 426 2011 19 and

1. 6%2. 469 2012 19 and

1. 4%2. 462 2013 19 and

1. 29%2. 496 2014 19 and

1. 17%2. 492 2015 1007 and

1. 65%2. 466 2016 19 and

1. 72%2. 452 2017 19 and

1. 22%2. 412 2018 19 and

1. 5%2. 425 2019 19 and

1. 82%2. 482 2020 1008 and

1. 49%2. 436 2021 22 and

1. 45%2. 440 2022 19 and

1. 35%2. 482 2024 1010 and

1. 16%2. 414 2026 19 and

1. 46%2. 482 2027 1010 and

1. 13%2. 418 2028 1012 and

1. 39%2. 440 2029 19 and

1. 55%2. 382 2030 19 and

1. 39%2. 378 2033 19 and

1. 71%2. 482 2034 1013 and

1. 45%2. 487.9 2035 1014 and

1. 22%2. 461.8 2036 1015 and

1. 27%2. 405.9 2037 87.1 and

1. 26%2. 392.0 2038 1016 and

1. 28%2. 433.8 2039 1017 and

1. 34%2. 473.9 2040 19 and

1. 34%2. 525 2041 23.15E and

1. 67%2. 482 2042 1300 and 1027

1. 33%2. 440 2043 1203 and 1027

1. 24%2. 468 2044 19 and

1. 26%2. 466 2046 19.2 and

1. 27%2. 535 2047 23.15F and

1. 74%2. 468 2048 23.15F and

1. 68%2. 468 2049 19 and

1. 31%2. 462 2050 23.15F and

1. 41%2. 496 2051 19 and

1. 66%2. 490 2052 19 and

1. 43%2. 490 2053 19 and

1. 76%2. 440 2054 1024 and

1. 15%2. 473 2055 19 and

1. 87%2. 454 2056 23.15F and

1. 52%2. 516 2056A 23.15F and

1. 62%2. 482 2057 23.15F and

1. 40%2. 482 2058 23.15F and

1. 71%2. 482 2059 1023 and

1. 67%2. 482 2060 1023 and

1. 60%2. 524 2061 19 and

1. 34%2. 448 2062 19 and

1. 43%2. 506 2063 19 and

1. 53%2. 490 2064 19 and

1. 25%2. 452 2065 19 and

1. 24%2. 480 2066 19 and

1. 37%2. 465 2067 19 and

1. 38%2. 458 2068 19 and

1. 35%2. 490 2069 19 and

1. 73%2. 482 2070 19 and

1. 69%2. 464 2071 19 and

1. 71%2. 494 2072 1022 and

1. 54%2. 467 2074 13.32A and 1028

1. 42%2. 482 2075 19 and

1. 78%2. 450 2076 19 and

1. 25%2. 402

1. A compound of the formula:

and the pharmaceutically acceptable salts and solvates thereof, wherein:A is selected from the group consisting of:

 wherein said A group is substituted with 1 to 6 substituents eachindependently selected from the group consisting of: unsubstitutedalkyl;

 wherein said A group is substituted with 1 to 6 substituents eachindependently selected from the group consisting of: unsubstitutedalkyl;

 wherein one or both rings of said A group is substituted with 1 to 6substituents each independently selected from the group consisting of:unsubstituted alkyl;

 wherein one or both rings of said A group is substituted with 1 to 6substituents each independently selected from the group consisting of:unsubstituted alkyl; B is:

 wherein R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴,

n is 0; R² is selected from the group consisting of: hydrogen, OH,—C(O)OH, —SH, —SO₂NR¹³R¹⁴, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³;R⁴ is independently selected from the group consisting of: hydrogen,cyano, halogen, alkyl, alkoxy, —OH, —CF₃, —OCF₃, —NO₂, —C(O)R¹³,—C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴, —SO_((t))R¹³,—C(O)NR¹³OR¹⁴, and unsubstituted or substituted aryl, wherein there are1 to 6 substituents on said substituted aryl group and each substituentis independently selected from the group consisting of: R⁹ groups; eachR⁵ and R⁶ are the same or different and are independently selected fromthe group consisting of hydrogen, halogen, alkyl, alkoxy, —CF₃, —OCF₃,—NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—C(O)NR¹³OR¹⁴, cyano, and unsubstituted aryl; each R⁷ and R⁸ isindependently selected from the group consisting of: H, unsubstituted orsubstituted alkyl, unsubstituted or substituted cycloalkyl, alkynyl andalkenyl; and wherein there are one or more substituents on saidsubstituted R⁷ and R⁸ groups, wherein each substituent is independentlyselected from the group consisting of: a) halogen, b) —CF₃, c) —COR¹³,d) —OR¹³, e) —NR¹³R¹⁴, f) —NO₂, g) —CN, h) —SO₂OR¹³, i) —CO₂R¹³, j)—C(O)NR¹³R¹⁴, k) —NR¹³C(O)R¹⁴, and l) —NR¹³CO₂R¹⁴; each R⁹ isindependently selected from the group consisting of: —R¹³; each R¹³ andR¹⁴ is independently selected from the group consisting of: H andunsubstituted alkyl; each R¹⁵ is independently selected from the groupconsisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl; R¹⁷is selected from the group consisting of: —SO₂alkyl, —SO₂aryl,—SO₂cycloalkyl, and —SO₂heteroaryl; R³⁰ is selected from the groupconsisting of: alkyl, cycloalkyl, —CN, —NO₂, or —SO₂R¹⁵ provided thatR¹⁵ is not H; and t is 0, 1 or
 2. 2. The compound of claim 1 wherein Bis:


3. The compound of claim 1 wherein B is:

R² is —OH, and R¹³ and R¹⁴ are each the same or different alkyl group.4. The compound of claim 1 wherein B is:

R³ selected from the group consisting of:


5. The compound of claim 1 wherein B is:

and R² is —OH.
 6. The compound of claim 1 wherein B is

R¹³ and R¹⁴ are each the same or different alkyl group.
 7. The compoundof claim 1 wherein B is


8. The compound of claim 7 wherein R² —OH.
 9. The compound of claim 7wherein R¹³ and R¹⁴ are the same or different alkyl group.
 10. Thecompound of claim 9 wherein the R² substituent is —OH.
 11. The compoundof claim 9 wherein R¹³ and R¹⁴ methyl.
 12. The compound of claim 11wherein the R² substituent is —OH.
 13. The compound of claim 1 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 14. The compoundof claim 1 wherein A is

wherein the furan ring is substituted.
 15. The compound of claim 1wherein A is

wherein the furan ring is substituted with at least one alkyl group. 16.The compound of claim 13 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 17. The compound of claim 16wherein R⁷ is H, and R⁸ is alkyl.
 18. The compound of claim 15 whereinR⁷ and R⁸ are independently selected from the group consisting of: H andalkyl.
 19. The compound of claim 18 wherein R⁷ is H, and R⁸ is alkyl.20. The compound of claim 1 wherein A is selected from the groupconsisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: alkyl, R⁷ is selected from the group consisting of:H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; andR⁸ is H.
 21. The compound of claim 2 wherein A is

wherein the furan ring is unsubstituted or substituted.
 22. The compoundof claim 2 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 23.The compound of claim 22 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 24. The compound of claim 23wherein R⁷ is H and R⁸ is alkyl.
 25. The compound of claim 3 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 26. The compoundof claim 25 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 27.The compound of claim 26 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 28. The compound of claim 27wherein R⁷ is H and R⁸ is alkyl.
 29. The compound of claim 7 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 30. The compoundof claim 7 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 31.The compound of claim 30 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 32. The compound of claim 31wherein R⁷ is H and R⁸ is alkyl.
 33. The compound of claim 8 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 34. The compoundof claim 8 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 35.The compound of claim 34 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 36. The compound of claim 35wherein R⁷ is H and R⁸ is alkyl.
 37. The compound of claim 10 wherein Ais

wherein the furan ring is unsubstituted or substituted.
 38. The compoundof claim 10 wherein A is

wherein the furan ring is substituted with at least one alkyl group. 39.The compound of claim 38 wherein R⁷ and R⁸ are independently selectedfrom the group consisting of: H and alkyl.
 40. The compound of claim 39wherein R⁷ is H and R⁸ is alkyl.
 41. The compound of claim 1 wherein:(1) A is selected from the group consisting of:

 wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: alkyl, R⁷ is selected from the group consisting of:H, —CF₃, —CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; andR⁸ is H; and (2) B is:

 wherein: R² is selected from the group consisting of: H, OH, —NHC(O)R¹³and —NHSO₂R¹³; R⁴ is selected from the group consisting of: H, —NO₂,cyano, —CH₃ or —CF₃; R⁵ is selected from the group consisting of: H,—CF₃, —NO₂, halogen and cyano; and R⁶ is selected from the groupconsisting of: H, alkyl and —CF₃; and each R¹³ and R¹⁴ is independentlyselected from the group consisting of: methyl and ethyl.
 42. Thecompound of claim 1 wherein (1) A is selected from the group consistingof:

 wherein: R² is —OH; R⁴ is selected form the group consisting of: H,—CH₃ and —CF₃; R⁵ is selected from the group consisting of: H and cyano;R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃; R¹³ andR¹⁴ are methyl.
 43. The compound of claim 1 wherein said compound is acalcium salt.
 44. The compound of claim 1 wherein said compound is asodium salt.
 45. The compound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 46. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 47. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 48. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 49. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 50. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 51. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 52. Thecompound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt or solvate thereof.
 53. Thecompound of claim 1 selected from the group consisting of


54. The compound of claim 53 wherein said compound is a calcium orsodium salt.
 55. The compound of claim 47 wherein said compound is acalcium or sodium salt.
 56. The compound of claim 48 wherein saidcompound is a calcium or sodium salt.
 57. A pharmaceutical compositioncomprising an effective amount of a compound of claim 1 in combinationwith a pharmaceutically acceptable carrier.
 58. The compound of claim 1wherein said compound is selected from the group consisting of:


59. The compound of claim 1 selected from the group consisting of:


60. The compound of claim 1 selected from the group consisting of:


61. The compound of claim 1 selected from the group consisting of:


62. The compound of claim 1 wherein said compound is:


63. The compound of claim 1 wherein said compound is:


64. The compound of claim 1 wherein said compound is:


65. The compound of claim 1 wherein said compound is:


66. The compound of claim 1 wherein said compound is:


67. The compound of claim 1 wherein said compound is:


68. The compound of claim 1 wherein said compound is:


69. The compound of claim 1 wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 70. The compound of claim1 wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 71. The compound of claim1 wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 72. The compound of claim1 wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 73. The compound of claim1 wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 74. The compound of claim1 wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 75. The compound of claim1 wherein said compound is:

or a pharmaceutically acceptable salt thereof.
 76. The compound of claim1 selected from the group consisting of:


77. The compound of claim 61 wherein said compound is a calcium orsodium salt.
 78. The compound of claim 76 wherein said compound is acalcium or sodium salt.
 79. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof.
 80. Thecompound of claim 79 wherein said compound is a calcium or sodium salt.81. A compound having the formula


82. A compound having the formula

or a pharmaceutically acceptable salt thereof.